Invasive Non-Typhoidal Salmonellosis

Infectious Disease MONDO:0017944 Pathograph 21 Show in embeddings browser Bacterial Infection salmonellosis

Invasive non-typhoidal salmonellosis is extraintestinal infection, most often bacteremia and sometimes meningitis or focal sterile-site infection, caused by non-typhoidal serovars of Salmonella enterica. In sub-Saharan Africa, the disease is driven largely by invasive Salmonella Typhimurium ST313 and Salmonella Enteritidis pathovars in infants, young children, and immunocompromised adults; HIV infection, malaria, malnutrition, anemia, and sickle cell disease are major host contexts for invasion.

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1
Definitions
7
Pathophys.
8
Phenotypes
1
Gaps
21
Pathograph
9
Genes
4
Medical Actions
1
Subtypes
5
Trials
1
Models
1
Deep Research
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
📘

Definitions

1
Extraintestinal non-typhoidal Salmonella definition
Invasive non-typhoidal salmonellosis is bloodstream, meningeal, or other normally sterile-site infection by a non-typhoidal Salmonella serovar rather than self-limited gastroenteritis.
OTHER
Show evidence (1 reference)
PMID:35114140 SUPPORT Human Clinical
"Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included."
The systematic review defines iNTS disease through culture of non-typhoidal Salmonella from blood, bone marrow, or another normally sterile site.
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Subtypes

1
S. Typhimurium ST313 invasive NTS disease (sub-Saharan Africa)
Invasive NTS disease caused by the Salmonella Typhimurium sequence type ST313 lineage, currently lineage 2 (ST313-L2). The defining determinant is the sequence type itself: ST313 is a genomically distinct clade within S. Typhimurium, carrying pseudogenes and deletions that the gastroenteritis-associated ST19 lineage does not, and it is a lineage below any rank NCBITaxon names, so it is carried structurally here with no identifier rather than bound to `NCBITaxon:90371`, its parent serovar. It differs from the other serovars in this entry on geography (a sub-Saharan African clade), on presentation (bloodstream infection, septicaemia and meningitis rather than gastroenteritis), on at-risk population (HIV in adults; malaria, HIV and malnutrition in children) and on drug susceptibility (multidrug-resistant, which has forced more expensive regimens).
Show evidence (5 references)
PMID:22587967 SUPPORT REVIEW SYNTHESIS Human Clinical
"A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause invasive disease in human beings."
Names the lineage and its sub-Saharan African range, the geographic axis on which this stratum differs from its sibling serovars.
PMID:22587967 SUPPORT REVIEW SYNTHESIS Human Clinical
"Multidrug-resistant ST313 has caused epidemics in several African countries, and has driven the use of expensive antimicrobial drugs in the poorest health services in the world."
States the drug-susceptibility difference, a second documented axis and the one with the clearest treatment consequence.
PMID:22587967 SUPPORT REVIEW SYNTHESIS Other
"The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children."
Names the at-risk populations of the African invasive-NTS epidemic this lineage drives.
+ 2 more references
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Discussions and Knowledge Gaps

1
Which reservoir and exposure route sustain African invasive Salmonella Typhimurium ST313 and invasive Salmonella Enteritidis transmission?
KNOWLEDGE GAP OPEN gap_invasive_nts_african_reservoir
Attached to
transmission#Unresolved fecal-oral transmission route
African iNTS pathovars deviate from classic zoonotic foodborne Salmonella epidemiology, and recent genomic analyses support a human-to-human component; the environmental reservoir, infectious intermediates, and relative contributions of food, water, and anthroponotic spread remain unresolved.
Show evidence (1 reference)
PMID:40205197 SUPPORT Computational
"Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways."
The genomic census motivates the open question by supporting non-classic transmission routes for iNTS.
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Pathophysiology

7
Salmonella Peptidoglycan Cross-Linking (Beta-Lactam Target)
Salmonella enterica builds and maintains its peptidoglycan cell wall by penicillin-binding protein transpeptidase cross-linking. This conserved reaction is the target of beta-lactam antibiotics, including third-generation cephalosporins used for empiric iNTS therapy when locally active.
peptidoglycan-based cell wall biogenesis GO:0009273 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves peptidoglycan-based cell wall biogenesis (GO:0009273). GO:0009273 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:22203377 SUPPORT Other
"Peptidoglycan synthesis requires glycosyltransferases (GTases) to polymerize the glycan chains and DD-transpeptidases (DD-TPases) to crosslink the peptides"
The review establishes peptide cross-linking by DD-transpeptidases, also called penicillin-binding proteins, as an essential step in bacterial peptidoglycan synthesis.
Invasive NTS intestinal entry
Ingested Salmonella survives transit to the intestinal mucosa, where Salmonella pathogenicity-island systems can mediate epithelial or M-cell entry and deliver organisms to submucosal phagocytes.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology. M cell of gut CL:0000682 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves M cell of gut (CL:0000682). CL:0000682 is a cell type from the Cell Ontology.
symbiont entry into host cell GO:0046718 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves symbiont entry into host cell (GO:0046718). GO:0046718 is a biological process from the Gene Ontology.
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
ST313 macrophage survival and muted inflammasome signaling Translocated invasive NTS can be phagocytosed by macrophages and survive intracellularly.
Show evidence (1 reference)
DOI:10.1128/ecosalplus.esp-0001-2023 SUPPORT Other
"Salmonella pathogenicity islands (SPIs), which are scattered throughout different Salmonella genomes and encode factors essential for adhesion, invasion, survival, and replication within the host."
The Salmonella infection-biology review supports SPI-dependent adhesion and invasion as the initial host-entry mechanism.
ST313 macrophage survival and muted inflammasome signaling
The African invasive S. Typhimurium ST313 genotype survives and replicates in macrophages better than globally distributed gastroenteritis-associated ST19 strains; lower flagellin expression blunts macrophage inflammatory cytokine production and cell death, reducing early containment.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
development of symbiont in host GO:0044114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves development of symbiont in host (GO:0044114). GO:0044114 is a biological process from the Gene Ontology. symbiont-mediated perturbation of host innate immune response GO:0052167 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves symbiont-mediated perturbation of host innate immune response (GO:0052167). GO:0052167 is a biological process from the Gene Ontology.
Salmonella-containing vacuole GO:0020003 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Salmonella-containing vacuole, annotated with symbiont-containing vacuole (GO:0020003). GO:0020003 is a cellular component from the Gene Ontology.
Experimental models
ST313 macrophage infection cell models CO CULTURE The cultures directly assay the macrophage-intrinsic survival and muted cytokine response component of this organismal dissemination mechanism.
Downstream
Invasive NTS bacteremia Intramacrophage survival permits systemic spread to blood and reticuloendothelial tissues.
Show evidence (2 references)
PMID:25569606 SUPPORT In Vitro
"Here, we show that strains of the ST313 genotype are phagocytosed more efficiently and are highly resistant to killing by macrophage cell lines and primary mouse and human macrophages compared to ST19 strains."
Human and mouse macrophage experiments support the ST313 intracellular-survival phenotype.
PMID:25569606 SUPPORT In Vitro
"Infection of macrophages with S. Typhimurium ST19 strains resulted in increased apoptosis and higher production of proinflammatory cytokines, as measured by gene expression and protein production, compared to S. Typhimurium ST313 strains."
The same study links ST313 to lower macrophage apoptosis and reduced proinflammatory cytokine production relative to ST19.
Impaired IL-12 and interferon-gamma control of Salmonella
Impaired IL-12-dependent interferon-gamma signaling compromises macrophage control of intracellular Salmonella; rare Mendelian defects in this axis and a common STAT4 risk locus both support the pathway as a human susceptibility mechanism.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
regulation of type II interferon production GO:0032649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves regulation of type II interferon production (GO:0032649). GO:0032649 is a biological process from the Gene Ontology. macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology.
Downstream
Invasive NTS bacteremia Impaired IL-12/interferon-gamma macrophage activation can fail to contain intracellular Salmonella.
Show evidence (2 references)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Investigation of rare patients with primary immunodeficiencies has suggested a key role for interferon gamma-mediated immunity in host defense against NTS."
The review ties primary immunodeficiency evidence to interferon-gamma-mediated anti-NTS defense.
PMID:29523850 SUPPORT Human Clinical
"We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia."
The Kenyan and Malawian case-control study identifies STAT4 as a common-variant susceptibility locus for NTS bacteremia.
HIV-associated anti-LPS bactericidal blockade
HIV infection can produce high-titer antibodies against Salmonella LPS that block complement-mediated bactericidal activity, compounding cellular immune impairment in adults with HIV-associated iNTS disease.
complement activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology. humoral immune response GO:0006959 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves humoral immune response (GO:0006959). GO:0006959 is a biological process from the Gene Ontology.
Downstream
Invasive NTS bacteremia Loss of serum bactericidal activity favors survival after entry into blood.
Show evidence (1 reference)
PMID:20413503 SUPPORT In Vitro
"Killing was restored by genetically shortening LPS from the target Salmonella or removing LPS-specific antibodies from serum."
Serum bactericidal experiments show that HIV-associated anti-LPS antibodies can directly block Salmonella killing.
Invasive NTS bacteremia
Once iNTS organisms escape local gut containment and host bactericidal mechanisms, viable Salmonella in blood produces the non-specific febrile systemic syndrome and can seed meninges, joints, bone, and endovascular lesions.
response to bacterium GO:0009617 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to bacterium (GO:0009617). GO:0009617 is a biological process from the Gene Ontology.
blood UBERON:0000178 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood (UBERON:0000178). UBERON:0000178 is an anatomical location from the Uberon multi-species anatomy ontology. spleen UBERON:0002106 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spleen (UBERON:0002106). UBERON:0002106 is an anatomical location from the Uberon multi-species anatomy ontology. liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Fever Bloodstream Salmonella infection commonly presents as fever.
Bacteremia Viable non-typhoidal Salmonella in blood is the defining microbiologic phenotype.
Sepsis Uncontrolled bloodstream infection can progress to sepsis.
Shock Severe bloodstream infection with organ dysfunction can progress to shock.
Meningitis Meningeal seeding produces NTS meningitis, especially in infants.
Pneumonia Bloodstream infection can seed extraintestinal focal infections, including pulmonary infection.
Splenomegaly Sustained systemic infection in African iNTS commonly includes hepatosplenomegaly.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
The review identifies bacteremia and meningitis as core sterile-site manifestations of iNTS disease.
Antimicrobial-resistant invasive NTS
African invasive S. Typhimurium ST313 lineages have repeatedly acquired plasmid-borne and chromosomal resistance, including resistance relevant to fluoroquinolones and other agents, so therapy has to be guided by local and isolate-level susceptibility.
response to antibiotic GO:0046677 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to antibiotic (GO:0046677). GO:0046677 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:37872141 SUPPORT Computational
"We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance."
Genome analysis of 1303 African S. Typhimurium isolates supports acquired resistance as a treatment-modifying mechanism in invasive ST313 lineages.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Invasive Non-Typhoidal Salmonellosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Blood 1
Anemia FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Anemia can be an upstream malaria or malnutrition context, a coincident comorbidity, and a reported complication. This entry therefore records the phenotype but leaves the directionality unresolved.
Show evidence (2 references)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
The review lists anemia among the established clinical associations with iNTS disease.
PMID:35114140 SUPPORT Human Clinical
"followed by anaemia in 580 (47·3%) of 1225 participants."
The global systematic review reports anemia as a frequent complication in the iNTS studies that included it.
Cardiovascular 2
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22587967 SUPPORT Other
"The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent."
The review identifies hepatosplenomegaly as a common presentation of African iNTS disease.
Shock HP:0031273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shock (HP:0031273). HP:0031273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22261309 SUPPORT Human Clinical
"mycotic aneurysm (aOR 3·7, P=0·023) and shock (aOR 12·1, P<0·0001)"
The adult NTS bacteremia cohort identifies shock as a mortality-associated presentation.
Immune 3
Meningitis HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
Meningitis is named alongside bacteremia as an invasive NTS manifestation.
Sepsis FREQUENT HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35114140 SUPPORT Human Clinical
"The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants."
The global systematic review found septicemia to be the most prevalent reported iNTS complication.
Pneumonia HP:0002090 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumonia (HP:0002090). HP:0002090 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22261309 SUPPORT Human Clinical
"The most common EFIs in the elderly patients (⩾55 years) was mycotic aneurysm, followed by pulmonary infections and bone/joint infections."
The adult NTS bacteremia cohort identifies pulmonary infections among the most common extra-intestinal focal infections in elderly patients.
Metabolism 2
Fever FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"However, the clinical presentation of iNTS disease is often with fever alone, so clinical diagnosis is impossible without blood culture confirmation."
The review supports fever as a frequent but non-specific iNTS presentation.
Bacteremia HP:0031864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bacteremia (HP:0031864). HP:0031864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
Bacteremia is named as a core clinical manifestation of iNTS disease.
🧬

Genetic Associations

9
IL12B (IL-12p40 defects reduce IFN-gamma-dependent macrophage control of Salmonella)
Gene: IL12B hgnc:5970 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL12B (hgnc:5970). hgnc:5970 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:25453225 SUPPORT Human Clinical
"MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
MSMD-spectrum IL-12/IFN-gamma defects predispose to salmonellosis as well as mycobacterial disease.
PMID:25453225 SUPPORT Human Clinical
"Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
The MSMD review identifies IL12B as an autosomal IFN-gamma-immunity gene.
IL12RB1 (IL-12/IL-23 receptor beta-1 defects reduce IFN-gamma induction)
Gene: IL12RB1 hgnc:5971 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL12RB1 (hgnc:5971). hgnc:5971 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:25453225 SUPPORT Human Clinical
"MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
MSMD-spectrum IL-12/IFN-gamma defects predispose to salmonellosis as well as mycobacterial disease.
PMID:25453225 SUPPORT Human Clinical
"Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
The MSMD review identifies IL12RB1 as an autosomal IFN-gamma-immunity gene.
IFNGR1 (Interferon-gamma receptor 1 defects blunt macrophage activation by IFN-gamma)
Gene: IFNGR1 hgnc:5439 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IFNGR1 (hgnc:5439). hgnc:5439 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:25453225 SUPPORT Human Clinical
"MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
MSMD-spectrum IFN-gamma-response defects predispose to salmonellosis as well as mycobacterial disease.
PMID:25453225 SUPPORT Human Clinical
"The first genetic etiology of MSMD was discovered in 1996: bi-allelic null mutations of IFNGR1"
The MSMD review identifies IFNGR1 as the first MSMD gene discovered.
IFNGR2 (Interferon-gamma receptor 2 defects blunt macrophage activation by IFN-gamma)
Gene: IFNGR2 hgnc:5440 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IFNGR2 (hgnc:5440). hgnc:5440 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:25453225 SUPPORT Human Clinical
"MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
MSMD-spectrum IFN-gamma-response defects predispose to salmonellosis as well as mycobacterial disease.
PMID:25453225 SUPPORT Human Clinical
"MSMD-causing mutations have been identified in seven autosomal genes: IFNGR1 and IFNGR2, which encodes the accessory chain of IFN-γR"
The MSMD review identifies IFNGR2 as the accessory interferon-gamma receptor gene.
STAT1 (Partial STAT1 defects impair IFN-gamma signal transduction)
Gene: STAT1 hgnc:11362 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT1 (hgnc:11362). hgnc:11362 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:25453225 SUPPORT Human Clinical
"Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
The MSMD review identifies STAT1 as an autosomal IFN-gamma-immunity gene.
STAT4 (rs13390936 modifies risk of NTS bacteremia in African children)
Gene: STAT4 hgnc:11365 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT4 (hgnc:11365). hgnc:11365 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:29523850 SUPPORT Human Clinical
"We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia."
The GWAS and replication analysis identify STAT4 rs13390936 as an association locus for NTS bacteremia in Kenyan and Malawian children.
CYBB (NADPH-oxidase deficiency in CYBB-associated CGD increases risk of Salmonella bloodstream infection)
Gene: CYBB hgnc:2578 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYBB (hgnc:2578). hgnc:2578 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:25453225 SUPPORT Human Clinical
"CYBB (also known as gp91phox or NOX2) is an essential component of the NADPH oxidase complex."
The MSMD review places CYBB in the macrophage/NADPH-oxidase branch of IFN-gamma-dependent immunity.
PMID:37704015 SUPPORT Human Clinical
"We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients."
CGD patients, including those with CYBB defects, can develop Salmonella bloodstream infection.
NCF1 (NADPH-oxidase deficiency in NCF1-associated CGD increases risk of Salmonella bloodstream infection)
Gene: NCF1 hgnc:7660 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NCF1 (hgnc:7660). hgnc:7660 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:22876374 SUPPORT Other
"biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
GeneReviews identifies NCF1 as one of the autosomal recessive CGD genes.
PMID:37704015 SUPPORT Human Clinical
"We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients."
CGD patients, including those with NCF1 defects, can develop Salmonella bloodstream infection.
HBB (HBB-associated sickle cell disease is a host context for invasive Salmonella disease)
Gene: HBB hgnc:4827 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HBB (hgnc:4827). hgnc:4827 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
The review names sickle cell disease as an established clinical association with iNTS disease.
💊

Medical Actions

4
Susceptibility-guided antibiotic therapy
Action: antibiotic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Therapy NCIT:C15620
Agent: ceftriaxone CHEBI:29007 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ceftriaxone (CHEBI:29007). CHEBI:29007 is a therapeutic agent from Chemical Entities of Biological Interest. cefotaxime CHEBI:204928 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cefotaxime (CHEBI:204928). CHEBI:204928 is a therapeutic agent from Chemical Entities of Biological Interest. ciprofloxacin CHEBI:100241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ciprofloxacin (CHEBI:100241). CHEBI:100241 is a therapeutic agent from Chemical Entities of Biological Interest. azithromycin CHEBI:2955 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azithromycin (CHEBI:2955). CHEBI:2955 is a therapeutic agent from Chemical Entities of Biological Interest. meropenem CHEBI:43968 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses meropenem (CHEBI:43968). CHEBI:43968 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Invasive NTS requires antibiotics that are active in blood and intracellular compartments; agent choice should account for local resistance and isolate susceptibility because African iNTS lineages have evolved multidrug, fluoroquinolone, XDR, and pan-drug resistance.
Mechanism Target:
MODULATES Antimicrobial-resistant invasive NTS — Susceptibility-guided selection routes around resistance mechanisms that inactivate otherwise appropriate antibiotic classes.
INHIBITS Salmonella Peptidoglycan Cross-Linking (Beta-Lactam Target) — Third-generation cephalosporins inhibit the Salmonella PBP cross-linking reaction when the isolate remains susceptible.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Antimicrobial resistance is common and case fatality rates are high."
The review supports antimicrobial resistance as a common treatment-modifying feature of iNTS disease.
Antiretroviral therapy for HIV-associated susceptibility
Action: Antiretroviral TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antiretroviral Therapy (NCIT:C94631). NCIT:C94631 is a clinical intervention from the NCI Thesaurus. NCIT:C94631
Platform: Small molecule
Antiretroviral therapy addresses the dominant adult HIV host context and was associated with decreasing invasive NTS incidence after ART rollout in Gauteng Province, South Africa.
Mechanism Target:
MODULATES HIV-associated anti-LPS bactericidal blockade — ART treats the HIV infection context that permits this dysregulated Salmonella humoral response rather than neutralizing anti-LPS antibody directly.
Show evidence (1 reference)
PMID:28264046 SUPPORT Human Clinical
"A strong negative correlation was observed between decreasing iNTS incidence and increasing ART use from 2004 to 2013 (r = -0.94, p < .001)."
Province-level surveillance supports ART scale-up as a population intervention that reduced HIV-associated invasive NTS incidence.
Surgical source control for Salmonella mycotic aneurysm
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Open vascular reconstruction or endovascular aneurysm repair can be needed when Salmonella bacteremia seeds the arterial wall and creates a mycotic aneurysm.
Show evidence (1 reference)
PMID:29947649 SUPPORT Other
"For surgical treatment, the approaches included in situ reconstructions, extra-anatomic bypass, and endovascular stent repair."
The case series and literature review identifies open reconstruction/bypass and endovascular stent repair as surgical approaches used for Salmonella mycotic aneurysm.
Experimental iNTS vaccination
Action: vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
No iNTS vaccine is yet licensed, but O-antigen-based outer-membrane vesicle and Salmonella conjugate vaccines have shown early adult safety and immunogenicity and are advancing through clinical development.
Show evidence (2 references)
PMID:40907249 SUPPORT Human Clinical
"The iNTS-GMMA vaccine was immunogenic and did not show safety concerns precluding further development, supporting progression to further phase I and II clinical trials."
A 2025 first-in-human trial supports early safety and immunogenicity of one bivalent invasive NTS vaccine candidate.
PMID:41062830 SUPPORT Human Clinical
"These data warrant further evaluation of TSCV for protection against invasive Salmonella disease."
A 2025 phase 1 trial supports continued evaluation of a trivalent Salmonella conjugate vaccine that covers the two main invasive NTS serovars plus S. Typhi.
🌍

Environmental Factors

4
HIV infection host context
HIV infection is a major adult host context for invasive NTS disease in Africa.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
The review names HIV infection as an established iNTS host association.
Mechanism Target:
PREDISPOSES HIV-associated anti-LPS bactericidal blockade — HIV infection can dysregulate Salmonella-specific humoral immunity and create inhibitory anti-LPS antibodies that block serum killing.
Show evidence (1 reference)
PMID:20413503 SUPPORT BACKGROUND Human Clinical
"Nontyphoidal Salmonellae are a major cause of life-threatening bacteremia among HIV-infected individuals."
The study directly evaluates the HIV-associated humoral mechanism in African adults with iNTS susceptibility.
Malaria host context
Malaria is a pediatric risk context for acquiring invasive NTS disease.
Show evidence (1 reference)
PMID:31562022 SUPPORT Computational
"Malnourished children, those with recent malaria or sickle-cell anaemia, and adults with HIV infection are at particularly high risk of disease."
The GBD 2017 analysis names recent malaria as a high-risk host context for iNTS disease.
Mechanism Target:
PREDISPOSES Invasive NTS bacteremia — Recent or active malaria increases iNTS risk, but the intervening phagocyte, hemolysis, anemia, and nutritional mechanisms are not split into asserted human causal nodes in this entry.
Malnutrition host context
Malnutrition is a pediatric host context for invasive NTS disease.
Show evidence (1 reference)
PMID:22587967 SUPPORT REVIEW SYNTHESIS Other
"The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children."
The review identifies malnutrition as an important pediatric risk factor for African iNTS disease.
Mechanism Target:
PREDISPOSES Invasive NTS bacteremia — Malnutrition is an established epidemiologic association with African iNTS disease, but the specific causal intermediates are not asserted here.
Sickle cell disease host context
Sickle cell disease increases susceptibility to invasive Salmonella infection.
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
The review names sickle cell disease as an established clinical association with iNTS disease.
Mechanism Target:
PREDISPOSES Invasive NTS bacteremia — Sickle cell disease increases invasive NTS risk, especially osteomyelitis risk, through a combination of splenic dysfunction, hemolysis, and tissue infarction.
🔬

Diagnosis

1
Blood or cerebrospinal fluid culture
Culture of blood, cerebrospinal fluid, bone marrow, or another normally sterile site confirms invasive disease and distinguishes iNTS from typhoid, paratyphoid, malaria, and other non-specific febrile illnesses.
Show evidence (1 reference)
PMID:35114140 SUPPORT Human Clinical
"Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included."
The meta-analysis case definition supports sterile-site culture as the diagnostic anchor.
📈

Progression

1
Acute invasive infection
Duration: Days to weeks
iNTS presents as an acute febrile bloodstream or sterile-site infection that either resolves with effective therapy or progresses to septic shock, meningitis, focal metastatic infection, or death.
Show evidence (1 reference)
PMID:35114140 SUPPORT Human Clinical
"Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died."
The systematic review supports iNTS as a severe acute infection with frequent complications and substantial fatality.
📊

Prevalence

2
Global population
Annual Incidence Unknown
GBD 2017 modelled 535,000 iNTS cases worldwide in 2017.
Show evidence (1 reference)
PMID:31562022 SUPPORT Computational
"We estimated that 535 000 (95% uncertainty interval 409 000-705 000) cases of non-typhoidal salmonella invasive disease occurred in 2017"
The GBD 2017 model provides global annual incidence for iNTS disease.
Sub-Saharan Africa
Annual Incidence 34.5 per 100,000 (26.6–45.0) person-years 1–9 per 10,000 per year
GBD 2017 estimated the highest regional iNTS incidence in sub-Saharan Africa, with the rate expressed per 100,000 person-years.
Show evidence (1 reference)
PMID:31562022 SUPPORT Computational
"with the highest incidence in sub-Saharan Africa (34·5 [26·6-45·0] cases per 100 000 person-years)"
The GBD 2017 model provides the sub-Saharan Africa annual incidence and uncertainty interval.
🦠

Infectious Agent

4
Non-typhoidal Salmonella enterica
Invasive NTS disease is caused by extraintestinal infection with a restricted set of non-typhoidal S. enterica serovars, especially S. Typhimurium ST313 and S. Enteritidis in sub-Saharan Africa.
Salmonella enterica NCBITaxon:28901 NCBI Taxonomy (NCBITaxon)
Salmonella enterica subsp. enterica serovar Typhimurium Salmonella enterica subsp. enterica serovar Enteritidis Salmonella enterica subsp. enterica serovar Dublin
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
The review identifies Salmonella Typhimurium ST313 and Salmonella Enteritidis as the principal African invasive NTS pathovars.
Salmonella Typhimurium
Salmonella Typhimurium sequence type ST313 is a major African invasive NTS pathovar associated with bloodstream infection and meningitis.
Salmonella enterica serovar Typhimurium NCBITaxon:90371 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
The review identifies S. Typhimurium ST313 as one of the dominant African invasive NTS pathovars.
Salmonella Enteritidis
Salmonella Enteritidis is the other major African invasive NTS pathovar named alongside S. Typhimurium ST313.
Salmonella enterica serovar Enteritidis NCBITaxon:149539 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:30657108 SUPPORT REVIEW SYNTHESIS Other
"Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
The review identifies S. Enteritidis as a principal African invasive NTS pathovar.
Salmonella Dublin
Salmonella Dublin is a non-typhoidal S. enterica serovar with a relatively invasive human clinical phenotype.
Salmonella enterica serovar Dublin NCBITaxon:98360 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:26996313 SUPPORT Computational
"Salmonella enterica subsp. enterica serovar Dublin (S. Dublin) is one of the non-typhoidal Salmonella (NTS); however, a relatively high proportion of human infections are associated with invasive disease."
Whole-genome analysis of invasive and non-invasive clinical S. Dublin isolates supports S. Dublin as an invasive non-typhoidal serovar.
↔️

Transmission

1
Unresolved fecal-oral transmission route
Non-typhoidal Salmonella can be acquired by a fecal-oral route, but the reservoir that sustains African iNTS pathovars is unresolved: classic foodborne zoonotic exposure does not fully explain ST313 epidemiology, and recent genomic work supports possible human-to-human transmission.
Show evidence (1 reference)
PMID:40205197 SUPPORT Computational
"Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways."
The 2025 genomic census supports anthroponotic transmission as a plausible component of iNTS spread, while retaining the uncertainty in the wording.
⚖️

Clinical Burden

High
Invasive NTS imposes high acute burden because it is a bloodstream or other sterile-site infection with frequent complications and double-digit pooled case-fatality ratios, especially in Africa and in immunocompromised hosts.
Show evidence (2 references)
PMID:35114140 SUPPORT Human Clinical
"From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3)."
The systematic review estimated an overall pooled case-fatality ratio of 14.7%.
PMID:35114140 SUPPORT Human Clinical
"When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa"
Region-stratified pooled CFR shows particularly high mortality in Africa.
🔬

Clinical Trials

5
NCT03981952 PHASE_I COMPLETED
Phase 1 randomized, placebo-controlled dose-escalation trial of trivalent S. Enteritidis, S. Typhimurium, and S. Typhi Vi conjugate vaccine in healthy United States adults.
Show evidence (1 reference)
clinicaltrials:NCT03981952 SUPPORT Human Clinical
"This is a randomized, placebo-controlled dose-escalation study."
ClinicalTrials.gov records this TSCV invasive Salmonella vaccine study as a randomized dose-escalation trial.
NCT05525546 PHASE_I COMPLETED
Phase 1 randomized, placebo-controlled study comparing full-strength, half-strength, and dilutional half-strength trivalent Salmonella conjugate vaccine formulations.
Show evidence (1 reference)
clinicaltrials:NCT05525546 SUPPORT Human Clinical
"This is a randomized, placebo-controlled interventional study."
ClinicalTrials.gov records this as an interventional randomized TSCV dose-formulation study.
NCT05480800 PHASE_II COMPLETED
Phase 1/2a observer-blind, randomized, controlled, two-stage multicountry study of the GSK/GVGH iNTS-typhoid conjugate vaccine in healthy European and African adults.
Show evidence (1 reference)
clinicaltrials:NCT05480800 SUPPORT Human Clinical
"The study intervention will be evaluated in European adults in Stage 1 (a 2-step staggered design) followed by African adults in Stage 2."
ClinicalTrials.gov describes the staged phase 1/2a iNTS-TCV evaluation in European and African adults.
ISRCTN51750695 PHASE_I COMPLETED
Phase 1 randomized, double-blind, placebo-controlled Oxford trial of a bivalent iNTS-GMMA vaccine against invasive non-typhoid Salmonella.
Show evidence (2 references)
ICTRP:ISRCTN51750695 SUPPORT Human Clinical
"| Phase | Phase I |"
The WHO ICTRP record identifies the iNTS-GMMA vaccine trial as phase I.
ICTRP:ISRCTN51750695 SUPPORT Human Clinical
"| Recruitment status | Completed |"
The WHO ICTRP record reports the Oxford iNTS-GMMA trial as completed.
NCT07416461 NOT_APPLICABLE RECRUITING
VINS observational test-negative study evaluating whether malaria vaccination reduces invasive NTS risk in children younger than 5 years in the Kisantu Health Zone of the Democratic Republic of the Congo.
Show evidence (1 reference)
clinicaltrials:NCT07416461 SUPPORT Human Clinical
"Using a case-control (test-negative) design, the researchers will look at the malaria vaccination status of participants with and without iNTS infection to determine if the malaria vaccine protects against iNTS."
ClinicalTrials.gov records VINS as an observational malaria-vaccine effectiveness study with iNTS as the endpoint.
🧫

Experimental Models

1
ST313 macrophage infection cell models CO_CULTURE
THP-1, U937, J774, primary mouse macrophage, and human PBMC infection systems compare invasive S. Typhimurium ST313 strains with gastroenteritis-associated ST19 strains for macrophage uptake, survival, replication, cytokine induction, and cell death.
Salmonella Typhimurium ST313 infection Salmonella Typhimurium ST19 comparator infection
macrophage CL:0000235 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Cell source
Immortalized macrophage/monocyte lines, primary mouse macrophages, and human PBMCs
Culture
Host-cell monolayer infection assays with intracellular-survival and cytokine readouts
Publication
PMID:25569606
Pathograph links
ST313 macrophage survival and muted inflammasome signaling partially recapitulates fidelity: moderate observes: cellular The cultures directly assay the macrophage-intrinsic survival and muted cytokine response component of this organismal dissemination mechanism.
Limitations: The model does not reproduce the HIV, malaria, malnutrition, or sickle cell disease host contexts that gate human invasive NTS bacteremia.
Show evidence (1 reference)
PMID:25569606 SUPPORT In Vitro
"Here, we show that strains of the ST313 genotype are phagocytosed more efficiently and are highly resistant to killing by macrophage cell lines and primary mouse and human macrophages compared to ST19 strains."
The cell models reproduce increased ST313 uptake and macrophage survival relative to ST19.
Show evidence (1 reference)
PMID:25569606 SUPPORT In Vitro
"S. Typhimurium ST313 strains survived and replicated within different macrophages."
The primary in-vitro study describes macrophage infection as the system used to assay ST313 intracellular survival.
{ }

Source YAML

click to show 
name: Invasive Non-Typhoidal Salmonellosis
creation_date: '2026-09-27T11:01:35Z'
category: Infectious Disease
description: >-
  Invasive non-typhoidal salmonellosis is extraintestinal infection, most often
  bacteremia and sometimes meningitis or focal sterile-site infection, caused by
  non-typhoidal serovars of Salmonella enterica. In sub-Saharan Africa, the
  disease is driven largely by invasive Salmonella Typhimurium ST313 and
  Salmonella Enteritidis pathovars in infants, young children, and
  immunocompromised adults; HIV infection, malaria, malnutrition, anemia, and
  sickle cell disease are major host contexts for invasion.
disease_term:
  preferred_term: invasive non-typhoidal salmonellosis
  term:
    id: MONDO:0017944
    label: invasive non-typhoidal salmonellosis
parents:
- Bacterial Infection
- salmonellosis
synonyms:
- iNTS disease
- invasive non-typhoidal Salmonella disease
- invasive nontyphoidal Salmonella disease
- non-typhoidal Salmonella bacteremia
- NTS bloodstream infection
definitions:
- name: Extraintestinal non-typhoidal Salmonella definition
  definition_type: OTHER
  description: >-
    Invasive non-typhoidal salmonellosis is bloodstream, meningeal, or other
    normally sterile-site infection by a non-typhoidal Salmonella serovar rather
    than self-limited gastroenteritis.
  evidence:
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included."
    explanation: The systematic review defines iNTS disease through culture of non-typhoidal Salmonella from blood, bone marrow, or another normally sterile site.
has_subtypes:
- name: ST313
  display_name: S. Typhimurium ST313 invasive NTS disease (sub-Saharan Africa)
  classification: lineage
  geography:
  - Sub-Saharan Africa
  description: >-
    Invasive NTS disease caused by the Salmonella Typhimurium sequence type ST313
    lineage, currently lineage 2 (ST313-L2). The defining determinant is the sequence
    type itself: ST313 is a genomically distinct clade within S. Typhimurium,
    carrying pseudogenes and deletions that the gastroenteritis-associated ST19
    lineage does not, and it is a lineage below any rank NCBITaxon names, so it is
    carried structurally here with no identifier rather than bound to
    `NCBITaxon:90371`, its parent serovar. It differs from the other serovars in this
    entry on geography (a sub-Saharan African clade), on presentation (bloodstream
    infection, septicaemia and meningitis rather than gastroenteritis), on at-risk
    population (HIV in adults; malaria, HIV and malnutrition in children) and on
    drug susceptibility (multidrug-resistant, which has forced more expensive
    regimens).
  evidence:
  - reference: PMID:22587967
    reference_title: >-
      "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical
      disease in Africa."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as
      a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause
      invasive disease in human beings.
    explanation: >-
      Names the lineage and its sub-Saharan African range, the geographic axis on which
      this stratum differs from its sibling serovars.
  - reference: PMID:22587967
    reference_title: >-
      "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical
      disease in Africa."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multidrug-resistant ST313 has caused epidemics in several African countries, and
      has driven the use of expensive antimicrobial drugs in the poorest health
      services in the world.
    explanation: >-
      States the drug-susceptibility difference, a second documented axis and the one
      with the clearest treatment consequence.
  - reference: PMID:22587967
    reference_title: >-
      "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical
      disease in Africa."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      The most important risk factors are HIV infection in adults, and malaria, HIV,
      and malnutrition in children.
    explanation: >-
      Names the at-risk populations of the African invasive-NTS epidemic this lineage
      drives.
  - reference: PMID:25569606
    reference_title: >-
      Invasive Salmonella Typhimurium ST313 with naturally attenuated flagellin elicits
      reduced inflammation and replicates within macrophages.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S. Typhimurium ST313 strains are clinically associated with invasive systemic
      disease (bacteremia, septicemia, meningitis) rather than with gastroenteritis.
    explanation: >-
      The presentation difference between this lineage and the gastroenteritis-causing
      ST19 lineage of the same serovar. The quote is the introduction of a macrophage
      study stating the human clinical association, so it is graded on that clinical
      evidence and marked BACKGROUND.
  - reference: PMID:37872141
    reference_title: >-
      A genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic
      resistance in sub-Saharan Africa.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2
      driving the current pandemic.
    explanation: >-
      Identifies the specific lineage within ST313 that is current, from a genomic
      analysis of isolates across 19 African countries.
infectious_agent:
- name: Non-typhoidal Salmonella enterica
  infectious_agent_term:
    preferred_term: Salmonella enterica
    term:
      id: NCBITaxon:28901
      label: Salmonella enterica
  description: >-
    Invasive NTS disease is caused by extraintestinal infection with a restricted
    set of non-typhoidal S. enterica serovars, especially S. Typhimurium ST313
    and S. Enteritidis in sub-Saharan Africa.
  has_subtypes:
  - name: Salmonella enterica subsp. enterica serovar Typhimurium
  - name: Salmonella enterica subsp. enterica serovar Enteritidis
  - name: Salmonella enterica subsp. enterica serovar Dublin
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
    explanation: The review identifies Salmonella Typhimurium ST313 and Salmonella Enteritidis as the principal African invasive NTS pathovars.
- name: Salmonella Typhimurium
  infectious_agent_term:
    preferred_term: Salmonella enterica serovar Typhimurium
    term:
      id: NCBITaxon:90371
      label: Salmonella enterica subsp. enterica serovar Typhimurium
  description: >-
    Salmonella Typhimurium sequence type ST313 is a major African invasive NTS
    pathovar associated with bloodstream infection and meningitis.
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
    explanation: The review identifies S. Typhimurium ST313 as one of the dominant African invasive NTS pathovars.
- name: Salmonella Enteritidis
  infectious_agent_term:
    preferred_term: Salmonella enterica serovar Enteritidis
    term:
      id: NCBITaxon:149539
      label: Salmonella enterica subsp. enterica serovar Enteritidis
  description: >-
    Salmonella Enteritidis is the other major African invasive NTS pathovar
    named alongside S. Typhimurium ST313.
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Over the past ten years, it has emerged that iNTS disease in Africa is caused by distinct pathovars of Salmonella Typhimurium, belonging to sequence type ST313, and Salmonella Enteritidis."
    explanation: The review identifies S. Enteritidis as a principal African invasive NTS pathovar.
- name: Salmonella Dublin
  infectious_agent_term:
    preferred_term: Salmonella enterica serovar Dublin
    term:
      id: NCBITaxon:98360
      label: Salmonella enterica subsp. enterica serovar Dublin
  description: >-
    Salmonella Dublin is a non-typhoidal S. enterica serovar with a relatively
    invasive human clinical phenotype.
  evidence:
  - reference: PMID:26996313
    reference_title: Whole genome sequencing provides insights into the genetic determinants of invasiveness in Salmonella Dublin.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Salmonella enterica subsp. enterica serovar Dublin (S. Dublin) is one of the non-typhoidal Salmonella (NTS); however, a relatively high proportion of human infections are associated with invasive disease."
    explanation: Whole-genome analysis of invasive and non-invasive clinical S. Dublin isolates supports S. Dublin as an invasive non-typhoidal serovar.
transmission:
- name: Unresolved fecal-oral transmission route
  description: >-
    Non-typhoidal Salmonella can be acquired by a fecal-oral route, but the
    reservoir that sustains African iNTS pathovars is unresolved: classic
    foodborne zoonotic exposure does not fully explain ST313 epidemiology, and
    recent genomic work supports possible human-to-human transmission.
  evidence:
  - reference: PMID:40205197
    reference_title: Genomic census of invasive nontyphoidal Salmonella infections reveals global and local human-to-human transmission.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways."
    explanation: The 2025 genomic census supports anthroponotic transmission as a plausible component of iNTS spread, while retaining the uncertainty in the wording.
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:30657108
      reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: OTHER
      snippet: "Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
      explanation: iNTS is an acquired systemic bacterial infection, placing it in Harrison's Infectious Diseases Part.
pathophysiology:
- name: Salmonella Peptidoglycan Cross-Linking (Beta-Lactam Target)
  description: >-
    Salmonella enterica builds and maintains its peptidoglycan cell wall by
    penicillin-binding protein transpeptidase cross-linking. This conserved
    reaction is the target of beta-lactam antibiotics, including
    third-generation cephalosporins used for empiric iNTS therapy when locally
    active.
  role: therapeutic_vulnerability
  conforms_to: "bacterial_cell_wall_synthesis_inhibition#Peptidoglycan Cross-Linking by Penicillin-Binding Proteins"
  biological_processes:
  - preferred_term: peptidoglycan-based cell wall biogenesis
    term:
      id: GO:0009273
      label: peptidoglycan-based cell wall biogenesis
  evidence:
  - reference: PMID:22203377
    reference_title: "From the regulation of peptidoglycan synthesis to bacterial growth and morphology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Peptidoglycan synthesis requires glycosyltransferases (GTases) to
      polymerize the glycan chains and DD-transpeptidases (DD-TPases) to
      crosslink the peptides
    explanation: >-
      The review establishes peptide cross-linking by DD-transpeptidases, also
      called penicillin-binding proteins, as an essential step in bacterial
      peptidoglycan synthesis.
- name: Invasive NTS intestinal entry
  description: >-
    Ingested Salmonella survives transit to the intestinal mucosa, where
    Salmonella pathogenicity-island systems can mediate epithelial or M-cell
    entry and deliver organisms to submucosal phagocytes.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: M cell of gut
    term:
      id: CL:0000682
      label: M cell of gut
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  evidence:
  - reference: DOI:10.1128/ecosalplus.esp-0001-2023
    reference_title: "Infection biology of <i>Salmonella enterica</i>"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Salmonella pathogenicity islands (SPIs), which are scattered throughout different Salmonella genomes and encode factors essential for adhesion, invasion, survival, and replication within the host."
    explanation: The Salmonella infection-biology review supports SPI-dependent adhesion and invasion as the initial host-entry mechanism.
  downstream:
  - target: ST313 macrophage survival and muted inflammasome signaling
    description: Translocated invasive NTS can be phagocytosed by macrophages and survive intracellularly.
- name: ST313 macrophage survival and muted inflammasome signaling
  description: >-
    The African invasive S. Typhimurium ST313 genotype survives and replicates
    in macrophages better than globally distributed gastroenteritis-associated
    ST19 strains; lower flagellin expression blunts macrophage inflammatory
    cytokine production and cell death, reducing early containment.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  cellular_components:
  - preferred_term: Salmonella-containing vacuole
    term:
      id: GO:0020003
      label: symbiont-containing vacuole
  biological_processes:
  - preferred_term: development of symbiont in host
    term:
      id: GO:0044114
      label: development of symbiont in host
  - preferred_term: symbiont-mediated perturbation of host innate immune response
    term:
      id: GO:0052167
      label: symbiont-mediated perturbation of host innate immune response
  evidence:
  - reference: PMID:25569606
    reference_title: Invasive Salmonella Typhimurium ST313 with naturally attenuated flagellin elicits reduced inflammation and replicates within macrophages.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that strains of the ST313 genotype are phagocytosed more efficiently and are highly resistant to killing by macrophage cell lines and primary mouse and human macrophages compared to ST19 strains."
    explanation: Human and mouse macrophage experiments support the ST313 intracellular-survival phenotype.
  - reference: PMID:25569606
    reference_title: Invasive Salmonella Typhimurium ST313 with naturally attenuated flagellin elicits reduced inflammation and replicates within macrophages.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Infection of macrophages with S. Typhimurium ST19 strains resulted in increased apoptosis and higher production of proinflammatory cytokines, as measured by gene expression and protein production, compared to S. Typhimurium ST313 strains."
    explanation: The same study links ST313 to lower macrophage apoptosis and reduced proinflammatory cytokine production relative to ST19.
  downstream:
  - target: Invasive NTS bacteremia
    description: Intramacrophage survival permits systemic spread to blood and reticuloendothelial tissues.
- name: Impaired IL-12 and interferon-gamma control of Salmonella
  description: >-
    Impaired IL-12-dependent interferon-gamma signaling compromises macrophage
    control of intracellular Salmonella; rare Mendelian defects in this axis
    and a common STAT4 risk locus both support the pathway as a human
    susceptibility mechanism.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: regulation of type II interferon production
    term:
      id: GO:0032649
      label: regulation of type II interferon production
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Investigation of rare patients with primary immunodeficiencies has suggested a key role for interferon gamma-mediated immunity in host defense against NTS."
    explanation: The review ties primary immunodeficiency evidence to interferon-gamma-mediated anti-NTS defense.
  - reference: PMID:29523850
    reference_title: Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia."
    explanation: The Kenyan and Malawian case-control study identifies STAT4 as a common-variant susceptibility locus for NTS bacteremia.
  downstream:
  - target: Invasive NTS bacteremia
    description: Impaired IL-12/interferon-gamma macrophage activation can fail to contain intracellular Salmonella.
- name: HIV-associated anti-LPS bactericidal blockade
  description: >-
    HIV infection can produce high-titer antibodies against Salmonella LPS that
    block complement-mediated bactericidal activity, compounding cellular
    immune impairment in adults with HIV-associated iNTS disease.
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
  - preferred_term: humoral immune response
    term:
      id: GO:0006959
      label: humoral immune response
  evidence:
  - reference: PMID:20413503
    reference_title: Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Killing was restored by genetically shortening LPS from the target Salmonella or removing LPS-specific antibodies from serum."
    explanation: Serum bactericidal experiments show that HIV-associated anti-LPS antibodies can directly block Salmonella killing.
  downstream:
  - target: Invasive NTS bacteremia
    description: Loss of serum bactericidal activity favors survival after entry into blood.
- name: Invasive NTS bacteremia
  description: >-
    Once iNTS organisms escape local gut containment and host bactericidal
    mechanisms, viable Salmonella in blood produces the non-specific febrile
    systemic syndrome and can seed meninges, joints, bone, and endovascular
    lesions.
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: response to bacterium
    term:
      id: GO:0009617
      label: response to bacterium
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
    explanation: The review identifies bacteremia and meningitis as core sterile-site manifestations of iNTS disease.
  downstream:
  - target: Fever
    description: Bloodstream Salmonella infection commonly presents as fever.
  - target: Bacteremia
    description: Viable non-typhoidal Salmonella in blood is the defining microbiologic phenotype.
  - target: Sepsis
    description: Uncontrolled bloodstream infection can progress to sepsis.
  - target: Shock
    description: Severe bloodstream infection with organ dysfunction can progress to shock.
  - target: Meningitis
    description: Meningeal seeding produces NTS meningitis, especially in infants.
  - target: Pneumonia
    description: Bloodstream infection can seed extraintestinal focal infections, including pulmonary infection.
  - target: Splenomegaly
    description: Sustained systemic infection in African iNTS commonly includes hepatosplenomegaly.
- name: Antimicrobial-resistant invasive NTS
  description: >-
    African invasive S. Typhimurium ST313 lineages have repeatedly acquired
    plasmid-borne and chromosomal resistance, including resistance relevant to
    fluoroquinolones and other agents, so therapy has to be guided by local and
    isolate-level susceptibility.
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:37872141
    reference_title: A genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic resistance in sub-Saharan Africa.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance."
    explanation: Genome analysis of 1303 African S. Typhimurium isolates supports acquired resistance as a treatment-modifying mechanism in invasive ST313 lineages.
phenotypes:
- name: Fever
  category: Constitutional
  frequency: FREQUENT
  description: >-
    iNTS often presents as a non-specific febrile illness, sometimes with fever
    as the only distinguishing clinical feature before blood-culture confirmation.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "However, the clinical presentation of iNTS disease is often with fever alone, so clinical diagnosis is impossible without blood culture confirmation."
    explanation: The review supports fever as a frequent but non-specific iNTS presentation.
- name: Bacteremia
  category: Infectious
  description: Viable non-typhoidal Salmonella in blood is the principal sterile-site manifestation of iNTS disease.
  phenotype_term:
    preferred_term: Bacteremia
    term:
      id: HP:0031864
      label: Bacteremia
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
    explanation: Bacteremia is named as a core clinical manifestation of iNTS disease.
- name: Meningitis
  category: Neurological
  severity: SEVERE
  description: Bacterial meningitis is an uncommon but severe manifestation of invasive NTS disease.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis."
    explanation: Meningitis is named alongside bacteremia as an invasive NTS manifestation.
- name: Sepsis
  category: Infectious
  frequency: FREQUENT
  severity: SEVERE
  description: Septicemia is the most frequent pooled complication in the global iNTS complication meta-analysis.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants."
    explanation: The global systematic review found septicemia to be the most prevalent reported iNTS complication.
- name: Anemia
  category: Hematologic
  frequency: FREQUENT
  description: Anemia is a common comorbidity and reported complication in African iNTS series.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
    explanation: The review lists anemia among the established clinical associations with iNTS disease.
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by anaemia in 580 (47·3%) of 1225 participants."
    explanation: The global systematic review reports anemia as a frequent complication in the iNTS studies that included it.
  notes: >-
    Anemia can be an upstream malaria or malnutrition context, a coincident
    comorbidity, and a reported complication. This entry therefore records the
    phenotype but leaves the directionality unresolved.
- name: Pneumonia
  category: Respiratory
  description: Pneumonia and other pulmonary infections can occur as focal complications of NTS bacteremia.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:22261309
    reference_title: "Non-typhoidal Salmonella bacteraemia in elderly patients: an increased risk for endovascular infections, osteomyelitis and mortality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common EFIs in the elderly patients (⩾55 years) was mycotic aneurysm, followed by pulmonary infections and bone/joint infections."
    explanation: The adult NTS bacteremia cohort identifies pulmonary infections among the most common extra-intestinal focal infections in elderly patients.
- name: Splenomegaly
  category: Gastrointestinal
  description: African invasive NTS can present with hepatosplenomegaly as part of its systemic febrile syndrome.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:22587967
    reference_title: "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent."
    explanation: The review identifies hepatosplenomegaly as a common presentation of African iNTS disease.
- name: Shock
  category: Infectious
  severity: SEVERE
  description: Shock can complicate invasive NTS bacteremia and is a high-risk presentation.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:22261309
    reference_title: "Non-typhoidal Salmonella bacteraemia in elderly patients: an increased risk for endovascular infections, osteomyelitis and mortality."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mycotic aneurysm (aOR 3·7, P=0·023) and shock (aOR 12·1, P<0·0001)"
    explanation: The adult NTS bacteremia cohort identifies shock as a mortality-associated presentation.
diagnosis:
- name: Blood or cerebrospinal fluid culture
  description: >-
    Culture of blood, cerebrospinal fluid, bone marrow, or another normally
    sterile site confirms invasive disease and distinguishes iNTS from typhoid,
    paratyphoid, malaria, and other non-specific febrile illnesses.
  evidence:
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included."
    explanation: The meta-analysis case definition supports sterile-site culture as the diagnostic anchor.
environmental:
- name: HIV infection host context
  description: HIV infection is a major adult host context for invasive NTS disease in Africa.
  effect: Predisposes adults to invasive NTS disease.
  influences_mechanisms:
  - target: HIV-associated anti-LPS bactericidal blockade
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      HIV infection can dysregulate Salmonella-specific humoral immunity and
      create inhibitory anti-LPS antibodies that block serum killing.
    evidence:
    - reference: PMID:20413503
      reference_title: Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Nontyphoidal Salmonellae are a major cause of life-threatening bacteremia among HIV-infected individuals."
      explanation: The study directly evaluates the HIV-associated humoral mechanism in African adults with iNTS susceptibility.
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
    explanation: The review names HIV infection as an established iNTS host association.
- name: Malaria host context
  description: Malaria is a pediatric risk context for acquiring invasive NTS disease.
  effect: Predisposes children to invasive NTS disease.
  influences_mechanisms:
  - target: Invasive NTS bacteremia
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recent or active malaria increases iNTS risk, but the intervening
      phagocyte, hemolysis, anemia, and nutritional mechanisms are not split
      into asserted human causal nodes in this entry.
  evidence:
  - reference: PMID:31562022
    reference_title: "The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Malnourished children, those with recent malaria or sickle-cell anaemia, and adults with HIV infection are at particularly high risk of disease."
    explanation: The GBD 2017 analysis names recent malaria as a high-risk host context for iNTS disease.
- name: Malnutrition host context
  description: Malnutrition is a pediatric host context for invasive NTS disease.
  effect: Predisposes children to invasive NTS disease.
  influences_mechanisms:
  - target: Invasive NTS bacteremia
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Malnutrition is an established epidemiologic association with African iNTS
      disease, but the specific causal intermediates are not asserted here.
  evidence:
  - reference: PMID:22587967
    reference_title: "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children."
    explanation: The review identifies malnutrition as an important pediatric risk factor for African iNTS disease.
- name: Sickle cell disease host context
  description: Sickle cell disease increases susceptibility to invasive Salmonella infection.
  effect: Predisposes to invasive NTS disease.
  influences_mechanisms:
  - target: Invasive NTS bacteremia
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sickle cell disease increases invasive NTS risk, especially osteomyelitis
      risk, through a combination of splenic dysfunction, hemolysis, and tissue
      infarction.
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
    explanation: The review names sickle cell disease as an established clinical association with iNTS disease.
treatments:
- name: Susceptibility-guided antibiotic therapy
  description: >-
    Invasive NTS requires antibiotics that are active in blood and intracellular
    compartments; agent choice should account for local resistance and isolate
    susceptibility because African iNTS lineages have evolved multidrug,
    fluoroquinolone, XDR, and pan-drug resistance.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: ceftriaxone
      term:
        id: CHEBI:29007
        label: ceftriaxone
    - preferred_term: cefotaxime
      term:
        id: CHEBI:204928
        label: cefotaxime
    - preferred_term: ciprofloxacin
      term:
        id: CHEBI:100241
        label: ciprofloxacin
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
    - preferred_term: meropenem
      term:
        id: CHEBI:43968
        label: meropenem
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Antimicrobial-resistant invasive NTS
    treatment_effect: MODULATES
    description: Susceptibility-guided selection routes around resistance mechanisms that inactivate otherwise appropriate antibiotic classes.
  - target: Salmonella Peptidoglycan Cross-Linking (Beta-Lactam Target)
    treatment_effect: INHIBITS
    description: Third-generation cephalosporins inhibit the Salmonella PBP cross-linking reaction when the isolate remains susceptible.
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Antimicrobial resistance is common and case fatality rates are high."
    explanation: The review supports antimicrobial resistance as a common treatment-modifying feature of iNTS disease.
- name: Antiretroviral therapy for HIV-associated susceptibility
  description: >-
    Antiretroviral therapy addresses the dominant adult HIV host context and was
    associated with decreasing invasive NTS incidence after ART rollout in
    Gauteng Province, South Africa.
  treatment_term:
    preferred_term: Antiretroviral Therapy
    term:
      id: NCIT:C94631
      label: Antiretroviral Therapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: HIV-associated anti-LPS bactericidal blockade
    treatment_effect: MODULATES
    description: >-
      ART treats the HIV infection context that permits this dysregulated
      Salmonella humoral response rather than neutralizing anti-LPS antibody
      directly.
  evidence:
  - reference: PMID:28264046
    reference_title: "An association between decreasing incidence of invasive non-typhoidal salmonellosis and increased use of antiretroviral therapy, Gauteng Province, South Africa, 2003-2013."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong negative correlation was observed between decreasing iNTS incidence and increasing ART use from 2004 to 2013 (r = -0.94, p < .001)."
    explanation: Province-level surveillance supports ART scale-up as a population intervention that reduced HIV-associated invasive NTS incidence.
- name: Surgical source control for Salmonella mycotic aneurysm
  description: >-
    Open vascular reconstruction or endovascular aneurysm repair can be needed
    when Salmonella bacteremia seeds the arterial wall and creates a mycotic
    aneurysm.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:29947649
    reference_title: "Mycotic aneurysm due to Salmonella species: clinical experiences and review of the literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For surgical treatment, the approaches included in situ reconstructions, extra-anatomic bypass, and endovascular stent repair."
    explanation: The case series and literature review identifies open reconstruction/bypass and endovascular stent repair as surgical approaches used for Salmonella mycotic aneurysm.
- name: Experimental iNTS vaccination
  description: >-
    No iNTS vaccine is yet licensed, but O-antigen-based outer-membrane vesicle
    and Salmonella conjugate vaccines have shown early adult safety and
    immunogenicity and are advancing through clinical development.
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  therapeutic_modality: VACCINE
  evidence:
  - reference: PMID:40907249
    reference_title: "Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The iNTS-GMMA vaccine was immunogenic and did not show safety concerns precluding further development, supporting progression to further phase I and II clinical trials."
    explanation: A 2025 first-in-human trial supports early safety and immunogenicity of one bivalent invasive NTS vaccine candidate.
  - reference: PMID:41062830
    reference_title: "A combination typhoid and non-typhoidal Salmonella polysaccharide conjugate vaccine in healthy adults: a randomized, placebo-controlled phase 1 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data warrant further evaluation of TSCV for protection against invasive Salmonella disease."
    explanation: A 2025 phase 1 trial supports continued evaluation of a trivalent Salmonella conjugate vaccine that covers the two main invasive NTS serovars plus S. Typhi.
prevalence:
- population: Global population
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: UNKNOWN
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    GBD 2017 modelled 535,000 iNTS cases worldwide in 2017.
  evidence:
  - reference: PMID:31562022
    reference_title: "The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We estimated that 535 000 (95% uncertainty interval 409 000-705 000) cases of non-typhoidal salmonella invasive disease occurred in 2017"
    explanation: The GBD 2017 model provides global annual incidence for iNTS disease.
- population: Sub-Saharan Africa
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 34.5
  rate_low: 26.6
  rate_high: 45.0
  rate_denominator: PERSON_YEARS
  prevalence_class: BAND_1_5_PER_10000
  notes: >-
    GBD 2017 estimated the highest regional iNTS incidence in sub-Saharan
    Africa, with the rate expressed per 100,000 person-years.
  evidence:
  - reference: PMID:31562022
    reference_title: "The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "with the highest incidence in sub-Saharan Africa (34·5 [26·6-45·0] cases per 100 000 person-years)"
    explanation: The GBD 2017 model provides the sub-Saharan Africa annual incidence and uncertainty interval.
progression:
- phase: Acute invasive infection
  duration: Days to weeks
  notes: >-
    iNTS presents as an acute febrile bloodstream or sterile-site infection that
    either resolves with effective therapy or progresses to septic shock,
    meningitis, focal metastatic infection, or death.
  evidence:
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died."
    explanation: The systematic review supports iNTS as a severe acute infection with frequent complications and substantial fatality.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Invasive NTS imposes high acute burden because it is a bloodstream or other
    sterile-site infection with frequent complications and double-digit pooled
    case-fatality ratios, especially in Africa and in immunocompromised hosts.
  evidence:
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3)."
    explanation: The systematic review estimated an overall pooled case-fatality ratio of 14.7%.
  - reference: PMID:35114140
    reference_title: "Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa"
    explanation: Region-stratified pooled CFR shows particularly high mortality in Africa.
genetic:
- name: IL12B
  gene_term:
    preferred_term: IL12B
    term:
      id: hgnc:5970
      label: IL12B
  relationship_type: SUSCEPTIBILITY
  association: IL-12p40 defects reduce IFN-gamma-dependent macrophage control of Salmonella
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
    explanation: MSMD-spectrum IL-12/IFN-gamma defects predispose to salmonellosis as well as mycobacterial disease.
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
    explanation: The MSMD review identifies IL12B as an autosomal IFN-gamma-immunity gene.
- name: IL12RB1
  gene_term:
    preferred_term: IL12RB1
    term:
      id: hgnc:5971
      label: IL12RB1
  relationship_type: SUSCEPTIBILITY
  association: IL-12/IL-23 receptor beta-1 defects reduce IFN-gamma induction
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
    explanation: MSMD-spectrum IL-12/IFN-gamma defects predispose to salmonellosis as well as mycobacterial disease.
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
    explanation: The MSMD review identifies IL12RB1 as an autosomal IFN-gamma-immunity gene.
- name: IFNGR1
  gene_term:
    preferred_term: IFNGR1
    term:
      id: hgnc:5439
      label: IFNGR1
  relationship_type: SUSCEPTIBILITY
  association: Interferon-gamma receptor 1 defects blunt macrophage activation by IFN-gamma
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
    explanation: MSMD-spectrum IFN-gamma-response defects predispose to salmonellosis as well as mycobacterial disease.
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first genetic etiology of MSMD was discovered in 1996: bi-allelic null mutations of IFNGR1"
    explanation: The MSMD review identifies IFNGR1 as the first MSMD gene discovered.
- name: IFNGR2
  gene_term:
    preferred_term: IFNGR2
    term:
      id: hgnc:5440
      label: IFNGR2
  relationship_type: SUSCEPTIBILITY
  association: Interferon-gamma receptor 2 defects blunt macrophage activation by IFN-gamma
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis"
    explanation: MSMD-spectrum IFN-gamma-response defects predispose to salmonellosis as well as mycobacterial disease.
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSMD-causing mutations have been identified in seven autosomal genes: IFNGR1 and IFNGR2, which encodes the accessory chain of IFN-γR"
    explanation: The MSMD review identifies IFNGR2 as the accessory interferon-gamma receptor gene.
- name: STAT1
  gene_term:
    preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  relationship_type: SUSCEPTIBILITY
  association: Partial STAT1 defects impair IFN-gamma signal transduction
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered."
    explanation: The MSMD review identifies STAT1 as an autosomal IFN-gamma-immunity gene.
- name: STAT4
  gene_term:
    preferred_term: STAT4
    term:
      id: hgnc:11365
      label: STAT4
  relationship_type: SUSCEPTIBILITY
  association: rs13390936 modifies risk of NTS bacteremia in African children
  notes: >-
    STAT4 is a host susceptibility locus, not a monogenic cause of iNTS. The
    disease still requires Salmonella exposure and a permissive infectious or
    immune context.
  evidence:
  - reference: PMID:29523850
    reference_title: Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia."
    explanation: The GWAS and replication analysis identify STAT4 rs13390936 as an association locus for NTS bacteremia in Kenyan and Malawian children.
- name: CYBB
  gene_term:
    preferred_term: CYBB
    term:
      id: hgnc:2578
      label: CYBB
  relationship_type: SUSCEPTIBILITY
  association: NADPH-oxidase deficiency in CYBB-associated CGD increases risk of Salmonella bloodstream infection
  evidence:
  - reference: PMID:25453225
    reference_title: "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CYBB (also known as gp91phox or NOX2) is an essential component of the NADPH oxidase complex."
    explanation: The MSMD review places CYBB in the macrophage/NADPH-oxidase branch of IFN-gamma-dependent immunity.
  - reference: PMID:37704015
    reference_title: "Infections due to Salmonella sp. in children with chronic granulomatous disease: Our experience from North India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients."
    explanation: CGD patients, including those with CYBB defects, can develop Salmonella bloodstream infection.
- name: NCF1
  gene_term:
    preferred_term: NCF1
    term:
      id: hgnc:7660
      label: NCF1
  relationship_type: SUSCEPTIBILITY
  association: NADPH-oxidase deficiency in NCF1-associated CGD increases risk of Salmonella bloodstream infection
  evidence:
  - reference: PMID:22876374
    reference_title: "Chronic Granulomatous Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD"
    explanation: GeneReviews identifies NCF1 as one of the autosomal recessive CGD genes.
  - reference: PMID:37704015
    reference_title: "Infections due to Salmonella sp. in children with chronic granulomatous disease: Our experience from North India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found three patients with Salmonella sp. bloodstream infections (2-proven, 1-probable) among the 99 CGD patients."
    explanation: CGD patients, including those with NCF1 defects, can develop Salmonella bloodstream infection.
- name: HBB
  gene_term:
    preferred_term: HBB
    term:
      id: hgnc:4827
      label: HBB
  relationship_type: SUSCEPTIBILITY
  association: HBB-associated sickle cell disease is a host context for invasive Salmonella disease
  evidence:
  - reference: PMID:30657108
    reference_title: Invasive Nontyphoidal Salmonella Disease in Africa.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease."
    explanation: The review names sickle cell disease as an established clinical association with iNTS disease.
clinical_trials:
- name: NCT03981952
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase 1 randomized, placebo-controlled dose-escalation trial of trivalent
    S. Enteritidis, S. Typhimurium, and S. Typhi Vi conjugate vaccine in healthy
    United States adults.
  evidence:
  - reference: clinicaltrials:NCT03981952
    reference_title: "Phase 1 Randomized, Placebo-Controlled, Dose-Escalation Study of the Safety, Reactogenicity, and Immunogenicity of Trivalent (S. Enteritidis/S. Typhimurium/S. Typhi Vi) Conjugate Vaccine Against Invasive Salmonella Disease Administered Parenterally to Healthy U.S. Adults"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a randomized, placebo-controlled dose-escalation study."
    explanation: ClinicalTrials.gov records this TSCV invasive Salmonella vaccine study as a randomized dose-escalation trial.
- name: NCT05525546
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase 1 randomized, placebo-controlled study comparing full-strength,
    half-strength, and dilutional half-strength trivalent Salmonella conjugate
    vaccine formulations.
  evidence:
  - reference: clinicaltrials:NCT05525546
    reference_title: "Phase 1 Randomized, Placebo-Controlled, Study to Compare the Safety, Reactogenicity, and Immunogenicity of a Full-Strength Formulation of Trivalent Salmonella (S. Enteritidis/S. Typhimurium/S. Typhi Vi) Conjugate Vaccine (TSCV), a Half-Strength Formulation of TSCV, and a Dilutional Half-Strength Dose of TSCV Against Invasive Salmonella Disease Administered Parenterally to Healthy U.S. Adults"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a randomized, placebo-controlled interventional study."
    explanation: ClinicalTrials.gov records this as an interventional randomized TSCV dose-formulation study.
- name: NCT05480800
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase 1/2a observer-blind, randomized, controlled, two-stage multicountry
    study of the GSK/GVGH iNTS-typhoid conjugate vaccine in healthy European
    and African adults.
  notes: >-
    ClinicalTrials.gov normalizes this Phase 1/2a registry record to PHASE_II,
    so the local value follows the registry phase rather than the title's
    first-in-human wording.
  evidence:
  - reference: clinicaltrials:NCT05480800
    reference_title: "A Phase 1/2a, Observer-blind, Randomized, Controlled, Two-stage, Multi-country Study to Evaluate the Safety, Reactogenicity, and Immune Response of the Trivalent Vaccine Against Invasive Nontyphoidal Salmonella (iNTS) and Typhoid Fever in Healthy European and African Adults"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study intervention will be evaluated in European adults in Stage 1 (a 2-step staggered design) followed by African adults in Stage 2."
    explanation: ClinicalTrials.gov describes the staged phase 1/2a iNTS-TCV evaluation in European and African adults.
- name: ISRCTN51750695
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase 1 randomized, double-blind, placebo-controlled Oxford trial of a
    bivalent iNTS-GMMA vaccine against invasive non-typhoid Salmonella.
  evidence:
  - reference: ICTRP:ISRCTN51750695
    reference_title: Salmonella vaccine study in Oxford
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Phase | Phase I |"
    explanation: The WHO ICTRP record identifies the iNTS-GMMA vaccine trial as phase I.
  - reference: ICTRP:ISRCTN51750695
    reference_title: Salmonella vaccine study in Oxford
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Recruitment status | Completed |"
    explanation: The WHO ICTRP record reports the Oxford iNTS-GMMA trial as completed.
- name: NCT07416461
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    VINS observational test-negative study evaluating whether malaria
    vaccination reduces invasive NTS risk in children younger than 5 years in
    the Kisantu Health Zone of the Democratic Republic of the Congo.
  evidence:
  - reference: clinicaltrials:NCT07416461
    reference_title: Effectiveness of Malaria Vaccines in Reducing the Risk of Invasive Non-Typhoidal Salmonella Disease (VINS)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a case-control (test-negative) design, the researchers will look at the malaria vaccination status of participants with and without iNTS infection to determine if the malaria vaccine protects against iNTS."
    explanation: ClinicalTrials.gov records VINS as an observational malaria-vaccine effectiveness study with iNTS as the endpoint.
experimental_models:
- name: ST313 macrophage infection cell models
  description: >-
    THP-1, U937, J774, primary mouse macrophage, and human PBMC infection
    systems compare invasive S. Typhimurium ST313 strains with
    gastroenteritis-associated ST19 strains for macrophage uptake, survival,
    replication, cytokine induction, and cell death.
  experimental_model_type: CO_CULTURE
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - Salmonella Typhimurium ST313 infection
  - Salmonella Typhimurium ST19 comparator infection
  cell_source: Immortalized macrophage/monocyte lines, primary mouse macrophages, and human PBMCs
  culture_system: Host-cell monolayer infection assays with intracellular-survival and cytokine readouts
  publication: PMID:25569606
  modeled_mechanisms:
  - target: ST313 macrophage survival and muted inflammasome signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The cultures directly assay the macrophage-intrinsic survival and muted
      cytokine response component of this organismal dissemination mechanism.
    limitations: >-
      The model does not reproduce the HIV, malaria, malnutrition, or sickle
      cell disease host contexts that gate human invasive NTS bacteremia.
    evidence:
    - reference: PMID:25569606
      reference_title: Invasive Salmonella Typhimurium ST313 with naturally attenuated flagellin elicits reduced inflammation and replicates within macrophages.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we show that strains of the ST313 genotype are phagocytosed more efficiently and are highly resistant to killing by macrophage cell lines and primary mouse and human macrophages compared to ST19 strains."
      explanation: The cell models reproduce increased ST313 uptake and macrophage survival relative to ST19.
  evidence:
  - reference: PMID:25569606
    reference_title: Invasive Salmonella Typhimurium ST313 with naturally attenuated flagellin elicits reduced inflammation and replicates within macrophages.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "S. Typhimurium ST313 strains survived and replicated within different macrophages."
    explanation: The primary in-vitro study describes macrophage infection as the system used to assay ST313 intracellular survival.
discussions:
- discussion_id: gap_invasive_nts_african_reservoir
  prompt: Which reservoir and exposure route sustain African invasive Salmonella Typhimurium ST313 and invasive Salmonella Enteritidis transmission?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - transmission#Unresolved fecal-oral transmission route
  rationale: >-
    African iNTS pathovars deviate from classic zoonotic foodborne Salmonella
    epidemiology, and recent genomic analyses support a human-to-human
    component; the environmental reservoir, infectious intermediates, and
    relative contributions of food, water, and anthroponotic spread remain
    unresolved.
  evidence:
  - reference: PMID:40205197
    reference_title: Genomic census of invasive nontyphoidal Salmonella infections reveals global and local human-to-human transmission.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways."
    explanation: The genomic census motivates the open question by supporting non-classic transmission routes for iNTS.
notes: >-
  No host causal gene, disease-level inheritance pattern, or chromosomal
  abnormality is established for this acquired infection. Host genetics is
  represented only as susceptibility.
review_notes: >-
  Rung-3 lump/split review, 2026-10-03 (issue dismech#10115 decision 2; design decisions
  section 3e). Four strata were assessed on the six differentiating axes. The
  S. Typhimurium ST313 lineage is subtyped: it differs from its siblings on
  geography, presentation, at-risk population and drug susceptibility, each cited
  in the subtype row. S. Enteritidis and S. Dublin were deliberately kept lumped.
  Both are named in this entry as invasive serovars, which is why they are agents
  here at all, but that is the entry's inclusion criterion rather than a difference
  between them: searches of the cited literature (PubMed `"Salmonella Dublin"[tiab]
  AND invasive[tiab]`, `Enteritidis[tiab] AND "invasive non-typhoidal"[tiab]`, and
  the entry's own cached references) produced nothing quotable separating either
  one from ST313 disease on presentation, diagnosis, first-line therapy, prognosis,
  transmission route or at-risk population. In particular PMID:26996313, the
  whole-genome study behind the S. Dublin agent record, never mentions cattle or a
  bovine reservoir, so the bovine-reservoir difference that would be the obvious
  axis for that serovar cannot be cited from the sources this entry holds. Rule R10
  applies: both are candidates for a later subtype row if a source documents the
  difference.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Invasive Non-Typhoidal Salmonellosis · 2026-09-27T11:36:15Z · View source

Created a new invasive non-typhoidal salmonellosis entry from Claude Code deep research, modeling Salmonella intestinal entry, ST313 macrophage survival, impaired IL-12/interferon-gamma host control, HIV-associated anti-LPS bactericidal blockade, bloodstream dissemination, antimicrobial resistance, sterile-site phenotypes, culture diagnosis, susceptibility-guided antibiotics, experimental iNTS vaccination, GBD incidence, and STAT4 susceptibility.

Claude Code ▸
Invasive Non-Typhoidal Salmonellosis (iNTS Disease) — Comprehensive Research Report
claude-fable-5-1, claude-haiku-4-5-20251001, claude-opus-5 22 citations 2026-09-27T04:20:06.807351

Invasive Non-Typhoidal Salmonellosis (iNTS Disease) — Comprehensive Research Report

Target: Invasive Non-Typhoidal Salmonellosis · MONDO:0017944 · Category: Infectious Disease Report date: 2026-09-27 · Intended use: dismech knowledge-base entry population

Provenance note, read this first. Quotations marked [verbatim abstract] were retrieved as abstract text from PubMed Central, Europe PMC, or the publisher. Statements marked [tool-summarized] were paraphrased by a retrieval tool from the full text and are leads, not snippets. Before any of this becomes a dismech evidence.snippet, fetch the reference (just fetch-reference PMID:…) and confirm the exact substring; just count-verified-snippets and just validate-kb-references are the gates. All ontology CURIEs below were resolved live against EBI OLS4, HGNC REST, or NCBI Taxonomy during this session — none were written from memory — but dynamic-enum membership (e.g. whether an NCIT term is reachable from NCIT:C25218) was not checked and must be confirmed with just validate-terms.

1. Disease Information

Overview

Invasive non-typhoidal salmonellosis (iNTS disease) is extraintestinal infection — principally bloodstream infection, with meningitis and focal metastatic infection as important variants — caused by non-typhoidal serovars of Salmonella enterica. It is epidemiologically and clinically distinct from the self-limiting enterocolitis that the same serovars cause in high-income settings. In sub-Saharan Africa it presents as a non-specific febrile systemic illness resembling enteric fever, is caused predominantly by a small number of genetically distinct, human-adapted pathovars, carries a case-fatality ratio of roughly 15–20%, and occurs against a background of specific host comorbidities (HIV, malaria, malnutrition, anaemia, sickle cell disease).

[verbatim abstract, PMID:30657108] "Nontyphoidal salmonellae (NTS) are a major cause of invasive (iNTS) disease in sub-Saharan Africa, manifesting as bacteremia and meningitis. Available epidemiological data indicate that iNTS disease is endemic in much of the region. Antimicrobial resistance is common and case fatality rates are high. There are well-characterized clinical associations with iNTS disease, including young age, HIV infection, malaria, malnutrition, anemia, and sickle cell disease. However, the clinical presentation of iNTS disease is often with fever alone, so clinical diagnosis is impossible without blood culture confirmation."

The MONDO definition (retrieved live from OLS4) reads: "Invasive non-typhoidal salmonellosis (iNTS) is a rare bacterial infectious disease caused by extraintestinal infection of non-typhoidal serotypes of Salmonella enterica in patients with underlying HIV infection, malaria or malignancy. It has a high mortality rate and patients typically present with fever, pallor and respiratory signs (cough, tachnypnea, pneumonia). Gastrointestinal manifestations (diarrhea, vomit, abdominal pain) are not common. Occasionally, organ absseses, septic shock and meningitis may be observed." (Note: the MONDO text contains the typographical errors "tachnypnea" and "absseses"; if quoted as a dismech snippet, copy it verbatim including the errors, per the repository's snippet rule.)

Identifiers (verified)

Resource Identifier
MONDO MONDO:0017944 (label: invasive non-typhoidal salmonellosis; parent MONDO:0000827 salmonellosis)
Orphanet Orphanet:324648 (MONDO xref)
GARD GARD:0021449 (MONDO xref)
UMLS UMLS:C4706572 (MONDO xref)
MedGen MEDGEN:1638286 (MONDO xref)
SNOMED CT SCTID:763772002 (MONDO xref)
ICD-10 A02.1 Salmonella sepsis; A02.2 localized salmonella infections; A02.0 Salmonella enteritis; A02.9 Salmonella infection, unspecified (not present as MONDO xrefs; assign by curator judgement)
MeSH Salmonella Infections (D012480) — no iNTS-specific MeSH descriptor exists
OMIM Not applicable — iNTS is an acquired infection, not a Mendelian disorder. OMIM entries are relevant only to host susceptibility (see §4).
NCBITaxon (pathogens) NCBITaxon:28901 Salmonella enterica; NCBITaxon:90371 serovar Typhimurium; NCBITaxon:149539 serovar Enteritidis; NCBITaxon:98360 serovar Dublin

Synonyms

iNTS disease; invasive non-typhoidal Salmonella disease (both are MONDO exact synonyms); non-typhoidal Salmonella bacteraemia/bacteremia; NTS bloodstream infection; invasive salmonellosis (non-typhoidal). Note that "non-typhoidal salmonellosis" without "invasive" usually denotes the gastroenteritis phenotype and should not be treated as a synonym.

Data provenance character

Knowledge of this disease is overwhelmingly aggregate and hospital-based rather than patient-level EHR-derived. The Marchello meta-analysis found that [verbatim abstract, PMID:35114140] "Of these included studies, 77 (91·7%) were hospital-based and 66 (78·6%) were located in Africa or Asia… Of all 84 studies, 66 (78·6%) had an overall high risk of bias, 18 (21·4%) had a moderate risk, and none had a low risk." The most granular individual-level data come from single-site sentinel blood-culture surveillance (notably Malawi-Liverpool-Wellcome, Blantyre) and from genomic cohorts (§4, §6). No population-based registry exists.

2. Etiology

Causal factors

The necessary cause is infection by a non-typhoidal serovar of Salmonella enterica subsp. enterica. Serovar distribution is strikingly narrow for invasive disease:

  • Marchello et al. [tool-summarized, PMID:35114140, Table]: among 12,977 invasive isolates, Typhimurium 45.7%, Enteritidis 31.8%, Dublin 3.1%.
  • Blantyre, Malawi, 2011–2019 [tool-summarized, PMID:37153453]: S. Typhimurium 84.8%, S. Enteritidis 10.3%, other 4.9% of invasive isolates.
  • The Nature Medicine global genomic census identifies [verbatim abstract, PMID:40205197] "Salmonella Enteritidis identified as a major cause" outside Africa.

Within Typhimurium, the African invasive phenotype is carried by a specific sequence type: [verbatim abstract, PMID:37872141] "At least six invasive S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2 driving the current pandemic. ST313-L2 likely emerged in the Democratic Republic of Congo around 1980 and further spread in the mid 1990s."

Sufficiency requires a permissive host. The defining etiologic feature of iNTS disease is that invasion is comorbidity-gated: the same organisms cause enterocolitis in immunologically intact hosts.

Risk factors — host/comorbid (environmental in the dismech sense)

Risk factor Evidence
Advanced HIV infection (adults) [tool-summarized, PMID:22587967] "The main risk factor in adults is undoubtedly advanced HIV infection. Case series typically show 95% of adult cases to be in people infected with HIV." [tool-summarized, PMID:30657108] "iNTS disease in African adults is overwhelmingly HIV-associated, with rates of HIV coinfection in excess of 95%." Salmonella bacteraemia is an AIDS-defining infection [tool-summarized, PMID:35041743].
Malaria (children) Concurrent parasitaemia, recent malaria, and especially severe malarial anaemia are associated with iNTS disease [tool-summarized, PMID:30657108, PMID:22587967].
Malnutrition / acute severe malnutrition Recognized clinical association [verbatim abstract, PMID:30657108].
Anaemia Both as a marker and a risk factor; 47.3% of patients had anaemia as a complication [verbatim abstract, PMID:35114140].
Sickle cell disease [tool-summarized, PMID:30657108] "NTS is a common cause of invasive infection… in the context of sickle cell disease." Hallmark association with Salmonella osteomyelitis (HP:0005661). Relevant gene: HBB (hgnc:4827).
Young age Incidence peaks in infancy/second year of life. [verbatim abstract, PMID:40684736] "iNTS disease is observed from birth, with a peak incidence early in the second year of life, declining before the age of 3 years."
Older age (high-income settings) In a Taiwanese cohort of 272 adults with NTS bacteraemia, 162 (59.6%) were ≥55 years, with more extra-intestinal focal infections and higher 30-day mortality [tool-summarized, PMID:22261309].
Malignancy, corticosteroids, transplantation, haematologic malignancy Recognized risk groups in high-income settings [tool-summarized, PMID:35041743].
Sex [verbatim abstract, PMID:40205197] "Age and sex emerged as significant risk factors." Direction/magnitude should be read from that paper's tables, not assumed.

Risk factors — genetic (host susceptibility)

See §4 for detail. In brief: Mendelian defects of the IL-12/IFN-γ (type II interferon) axis, and a common-variant risk locus at STAT4.

Protective factors

  • Antiretroviral therapy reduced recurrence and incidence in HIV-infected adults. Pre-ART, [tool-summarized, PMID:22587967] "Before the antiretroviral therapy era 20–40% of survivors had recurrence, even after appropriate antimicrobial drugs."
  • Malaria control. A temporal association between falling malaria incidence and falling iNTS incidence has been reported from The Gambia, Kenya and Malawi [tool-summarized, PMID:30657108]. Modelling of Blantyre data attributes the paediatric decline jointly to malaria, HIV and malnutrition control [PMID:26230258].
  • Antibody-mediated immunity. [verbatim abstract, PMID:30657108] "immunoepidemiological studies from Africa indicate an important role for antibody for protective immunity, supporting the development of antibody-inducing vaccines against iNTS disease." This is the mechanistic rationale for the entire vaccine pipeline (§12, §13).
  • Genetic protective factors: no validated protective allele is established. The STAT4 finding is a risk allele; the alternative allele is protective by construction, not by independent demonstration. gnomAD allele frequencies for rs13390936 should be read directly rather than inferred.

Gene–environment interaction

The central interaction is host IFN-γ capacity × pathogen exposure. The STAT4 risk genotype is associated with reduced IFN-γ output, and the risk it confers is realized only in an exposed, comorbidity-burdened population [PMID:29523850]. A second, well-documented interaction is HIV × humoral immunity: HIV infection does not simply reduce antibody, it dysregulates it. MacLennan et al. showed that HIV-infected African adults have high-titre anti-LPS antibody that inhibits bactericidal killing [tool-summarized, PMID:20413503]. A third is malaria × phagocyte function, where haemolysis-derived haem and haem oxygenase-1 induction are proposed to impair neutrophil oxidative burst; treat this as mechanistically plausible and incompletely demonstrated in humans.

Risk factors are explicitly not independent: [tool-summarized, PMID:30657108] "HIV-infected South African children with NTS bacteremia are more likely to be malnourished than their HIV-uninfected counterparts."

3. Phenotypes

The defining phenotypic fact

There is no pathognomonic presentation. [tool-summarized, PMID:30657108] "The lack of a pathognomonic clinical presentation makes clinical diagnosis of iNTS disease impossible." [tool-summarized, PMID:22587967] "The clinical presentation of invasive non-typhoidal salmonella disease in Africa is typically febrile systemic illness resembling enteric fever; diarrhoea is often absent." For a dismech entry this means most phenotype nodes carry moderate-to-low specificity and several will legitimately bind coarse HPO terms — see the repository's coarse-phenotype-bindings guidance.

Presenting features with frequencies (African paediatric/adult series)

Frequencies below are [tool-summarized, PMID:30657108] study medians with ranges as reported in that review's tables.

Phenotype Frequency Suggested HP term
Fever median 97% (range 74–100%) HP:0001945 Fever
Tachypnea median 72% (66–77%) HP:0002789 Tachypnea
Diarrhoea (children) median 35% HP:0002014 Diarrhea
Splenomegaly median 31% (19–45%) HP:0001744 Splenomegaly
Hepatosplenomegaly common in series HP:0001433 Hepatosplenomegaly
Cough common HP:0012735 Cough
Pallor common (tracks anaemia) HP:0000980 Pallor
Respiratory distress common HP:0002098 Respiratory distress

Complications and their pooled prevalence

From the global meta-analysis [verbatim abstract, PMID:35114140]: "Among 55 studies reporting non-typhoidal salmonella disease-associated complications, a total of 45 different complications were reported and 1824 complication events were identified among 6974 study participants. The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants."

Additional complication frequencies [tool-summarized, PMID:35114140, Table 1] — treat every row as a lead requiring re-extraction from the paper, and note the authors' own finding that 78.6% of studies were at high risk of bias and that denominators differ per complication:

Complication Reported proportion Suggested HP term
Septicaemia 171/299 (57.2%) HP:0100806 Sepsis
Anaemia 580/1225 (47.3%) HP:0001903 Anemia
Shock 107/560 (19.1%) HP:0002615 Hypotension
Encephalopathy 8/40 (20.0%) HP:0001298 Encephalopathy
Pneumonia 232/1619 (14.3%) HP:0002090 Pneumonia
Septic shock 36/331 (10.9%) HP:0002615 Hypotension
Seizures 25/256 (9.8%) HP:0001250 Seizure
Extraintestinal focal infection 66/721 (9.2%) — (use specific focus)
Mycotic aneurysm 124/1991 (6.2%) no HP term; anchor to UBERON:0000947 aorta in pathophysiology
Recurrence 110/2299 (4.8%) HP:0002718 Recurrent bacterial infections
Abscess 47/1609 (2.9%) HP:0025059 Splenic abscess (if splenic)
Septic arthritis 16/566 (2.8%) HP:0003095 Septic arthritis
Osteomyelitis 38/1498 (2.5%) HP:0002754 Osteomyelitis / HP:0005661 Salmonella osteomyelitis
Endocarditis 6/366 (1.6%) HP:0100584 Endocarditis

The mycotic-aneurysm proportion is high relative to African series because the pooled denominator is dominated by East Asian adult cohorts; do not carry 6.2% into an African-context entry without stratification. This is a real example of aggregation across two different diseases-in-practice.

Meningitis as a distinct syndrome

Salmonella meningitis is uncommon but disproportionately lethal. [tool-summarized, PMID:35041743] case fatality "up to 50–70%" in recent reviews, with "mortality was ~20%" in African infants specifically. In Blantyre 2011–2019, 26 confirmed CSF-culture cases occurred, 88.5% S. Typhimurium, mostly in children [tool-summarized, PMID:37153453]. Suggested terms: HP:0001287 Meningitis; anatomy UBERON:0002360 meninx, UBERON:0001359 cerebrospinal fluid.

Laboratory abnormalities

Abnormality HP term
Anaemia HP:0001903
Thrombocytopenia HP:0001873
Increased total leukocyte count HP:0001974
Decreased total neutrophil count HP:0001875
Elevated CRP HP:0011227
Increased circulating lactate HP:0002151
Hypoglycaemia HP:0001943
Jaundice HP:0000952
Disseminated intravascular coagulation HP:0005521
Haemophagocytosis HP:0012156

Haemophagocytic lymphohistiocytosis due to fulminant Salmonella sepsis has been reported specifically in IL-12Rβ1 deficiency, linking a laboratory phenotype to a host-genetic mechanism (see §4).

Onset, severity, progression, and quality of life

  • Onset: acute, over days. Not congenital, not late-onset in the Mendelian sense. Age of occurrence peaks in infancy/second year of life in Africa [PMID:40684736] and in adults ≥55 years in high-income settings [PMID:22261309].
  • Severity: severe by definition of the entry (bloodstream/sterile-site infection), with pooled CFR ~15%.
  • Progression: acute and either resolving or fatal within days to weeks; recurrent/relapsing in HIV without ART (20–40% pre-ART recurrence [PMID:22587967]).
  • Quality of life: no iNTS-specific EQ-5D, SF-36, or PROMIS data were located. The GBD framework assigns disability weights via generic severe-infectious-episode and sequelae states; the 2021 analysis reports 4,740,235 DALYs (95% UI 2,762,282–7,597,208) [tool-summarized, DOI:10.1371/journal.pntd.0012960]. State plainly in the KB entry that per-phenotype QoL data are absent rather than substituting a generic sepsis instrument.

4. Genetic / Molecular Information

Causal genes: not applicable

iNTS disease has no causal human gene. Do not populate genetic: with a causal relationship_type for this entry. The genetics that matter are (a) host susceptibility and (b) pathogen genomics, which in dismech belong in genetic: with relationship_type: SUSCEPTIBILITY and in pathophysiology: respectively.

Host susceptibility — Mendelian

Defects of the IL-12/IL-23/IFN-γ axis (Mendelian susceptibility to mycobacterial disease, MSMD, and related inborn errors) predispose to non-typhoidal Salmonella invasive and recurrent disease. [tool-summarized, PMID:35041743] "conditions that compromise Th1 immune responses increase the risk," specifically "Mendelian mutations in the interleukin 12 (IL-12)/interferon γ (IFNγ) axis." The canonical review is Gilchrist, MacLennan & Hill, Nat Rev Immunol 2015 (PMID:26109132, DOI:10.1038/nri3858).

Genes to curate as susceptibility loci (HGNC verified live):

Gene HGNC Axis role
IL12B hgnc:5970 IL-12p40 subunit
IL12RB1 hgnc:5971 IL-12/IL-23 receptor β1
IFNGR1 hgnc:5439 IFN-γ receptor 1
IFNGR2 hgnc:5440 IFN-γ receptor 2
STAT1 hgnc:11362 Downstream transcription factor
IKBKG (NEMO) hgnc:5961 NF-κB signalling
CYBB hgnc:2578 Phagocyte NADPH oxidase (CGD)
NCF1 hgnc:7660 Phagocyte NADPH oxidase (CGD)
HBB hgnc:4827 Sickle cell disease (non-immune susceptibility)

For variant-level classification, ACMG/AMP calls, and allele frequencies, read ClinVar and gnomAD directly at curation time — this report does not assert variant-level pathogenicity, and none should be written into the entry from here.

Host susceptibility — common variant

[verbatim abstract, PMID:29523850] "Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia."

Field Value
Gene STAT4 (hgnc:11365)
Variant rs13390936, intronic
Model / effect recessive, OR 7.61 (95% CI 3.98–14.55) [tool-summarized]
Combined p 8.62 × 10⁻¹⁰ [tool-summarized]
Cohorts Kenyan discovery + Kenyan replication + Malawian replication
Functional support context-specific eQTL for STAT4 in stimulated immune cells; risk genotype associated with reduced IFN-γ production in stimulated NK cells and lower circulating IFN-γ during acute bacteraemia [tool-summarized]

Note the two published effect sizes differ by source (OR 7.2 in one summary, OR 7.61 recessive in another); resolve against the paper before recording a number.

Pathogen genomics — the substantive "molecular information" for this entry

ST313 lineage structure and dating [verbatim abstract, PMID:37872141]: "By analysing whole genome sequence data from 1303 S. Typhimurium isolates originating from 19 African countries and isolated between 1979 and 2017… At least six invasive S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2 driving the current pandemic. ST313-L2 likely emerged in the Democratic Republic of Congo around 1980 and further spread in the mid 1990s. We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance."

Supporting detail [tool-summarized, PMID:37872141]: MRCA of ST313-L2 dated 1980 (95% HPD 1974–1986); five independent introductions from DRC into East Africa 1995–2000; one major West African introduction (Ghana, 1994).

Sublineage displacement in Malawi [verbatim abstract, PMID:38623411]: "We performed an intensive comparative genomic analysis of 608 S. Typhimurium ST313 isolates dating between 1996 and 2018 from Blantyre, Malawi. We discovered that following the arrival of the well-characterized S. Typhimurium ST313 lineage 2 in 1999, two multidrug-resistant variants emerged in Malawi in 2006 and 2008, designated sublineages 2.2 and 2.3, respectively. The majority of S. Typhimurium isolates from human bloodstream infections in Malawi now belong to sublineages 2.2 or 2.3." Sublineage 2.2 shows constitutive SPI-2 expression under non-inducing conditions, reduced flagellar gene expression, a pCol1B9 plasmid with loss of pBT1, and a competitive fitness advantage [tool-summarized].

Genome degradation is the hallmark molecular signature: [verbatim abstract, PMID:25569606] "S. Typhimurium ST313 strains have acquired pseudogenes and genetic deletions and appear to be evolving to become more like the typhoidal serovars S. Typhi and S. Paratyphi A."

Antimicrobial resistance determinants [tool-summarized, PMID:37872141]: - MDR: cat (chloramphenicol), blaTEM (ampicillin), dfrA + sul (co-trimoxazole) - ESBL: blaCTX-M-15, blaSHV-12, blaOXA-1 - Azithromycin: mphA - Fluoroquinolone: chromosomal gyrA S83F/S83Y/D87G/D87N/D87Y, gyrB E466Y; plasmid-borne qnrB, qnrS, aac(6′)-Ib-cr - XDR and pan-drug resistance arose independently multiple times, associated with IncHI2 and IncI1 plasmids

Epigenetics and chromosomal abnormalities

Not applicable to the host. No DNA-methylation or histone-modification signature is established for iNTS susceptibility or pathogenesis, and no chromosomal abnormality causes this disease. If an epigenetic mechanism is curated at all, it belongs to the bacterium (Dam/Dcm methylation of Salmonella regulons) and should be marked as such, not as a host epigenetic change. Leave these fields empty with a notes: line recording that the literature was searched.

5. Environmental Information

Infectious agents

Agent NCBITaxon Role
Salmonella enterica NCBITaxon:28901 species
S. enterica serovar Typhimurium (esp. ST313 L2) NCBITaxon:90371 dominant African cause
S. enterica serovar Enteritidis NCBITaxon:149539 second most common; dominant in several non-African settings
S. enterica serovar Dublin NCBITaxon:98360 bovine-adapted, disproportionately invasive

Co-infecting agents that act as risk modifiers: Plasmodium falciparum (malaria), HIV-1.

Transmission and reservoir — a genuinely open question

This is the most important unresolved epidemiological issue and should be curated as a knowledge gap rather than settled. The classical NTS model is zoonotic foodborne transmission; the African iNTS pathovars appear not to follow it.

[tool-summarized, PMID:36910696] The sources of iNTS infections "remain unclear, with two main hypotheses: transmission from a zoonotic reservoir or person-to-person transmission." Two studies found isolates in stool of household members very closely related to the index iNTS isolate, "consistent with the hypothesis of person-to-person transmission, though infection from a common source cannot be excluded," and thorough investigation of the domestic environment and food pathway yielded "only a single iNTS-associated Salmonella Enteritidis isolate."

[verbatim abstract, PMID:40205197] "Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways."

Supporting host-restriction evidence [tool-summarized, PMID:30657108]: African invasive isolates "may be restricted, or be in the process of becoming restricted, to humans," with studies showing "isolated Salmonella strains in humans and animals were distinct," suggesting anthroponotic transmission.

Suggested dismech treatment: an environmental[] entry for the exposure route with environmental_effect: TRIGGERS linked to the colonization node, plus a discussions[] entry with kind: KNOWLEDGE_GAP on reservoir identity. ECTO binding for "exposure to Salmonella" should be searched at curation time; if nothing fits, record the queries run verbatim in notes: per the repository's negative-existence rule — do not write "no ECTO term exists" without the recorded searches.

Non-infectious environmental and lifestyle factors

  • Rainfall/seasonality: iNTS incidence in Malawi is seasonal, and rainfall was included as a covariate in the decline model (PMID:26230258).
  • Water, sanitation and hygiene: plausibly central given the person-to-person hypothesis, but no trial has demonstrated WASH impact on iNTS specifically. Curate as inferred, not demonstrated.
  • Food exposures (eggs, meat, dairy, produce) and overseas travel are established for NTS gastroenteritis in high-income settings and are the likely route for many high-income invasive cases; they are not established as the route for African iNTS.
  • No toxicological or occupational exposure is implicated. CTD/TOXNET yield nothing specific to this entry.

6. Mechanism / Pathophysiology

Ordered causal chain

The chain below is written for a dismech pathograph. Steps are numbered; branch points are explicit; where a step is inferred rather than demonstrated in humans, it is labelled.

  1. Ingestion of, or mucosal exposure to, an invasive NTS pathovar (ST313 L2 Typhimurium or invasive Enteritidis) leads to arrival of viable bacteria in the small intestine. Enhanced acid resistance of ST313 relative to ST19 promotes survival of gastric transit — D23580 "exhibited enhanced resistance to acid stress relative to SL1344, which may lend towards increased capability to survive passage through the gastrointestinal tract" [verbatim abstract, PMID:26091096]. Route in African settings is inferred (see §5).
  2. Intestinal epithelial and M-cell translocation (CL:0002563, CL:0000682; UBERON:0002108, UBERON:0001211) results in submucosal bacterial arrival. In ST313 this step is attenuated, not enhanced: ST313 shows "reduced SPI-1–mediated epithelial invasion" [tool-summarized, PMID:30657108]. This is the first mechanistic branch away from the gastroenteritis phenotype — less epithelial invasion means less enterocolitis, which is why diarrhoea is often absent.
  3. Phagocytosis by macrophages and monocytes (CL:0000235, CL:0000576; GO:0006909) leads to an intracellular niche. ST313 is taken up more efficiently than ST19: [verbatim abstract, PMID:25569606] "strains of the ST313 genotype are phagocytosed more efficiently and are highly resistant to killing by macrophage cell lines and primary mouse and human macrophages compared to ST19 strains."
  4. Intramacrophage survival and replication (GO:0030254 type III secretion; SPI-2) results in a replicating, sheltered bacterial population. [verbatim abstract, PMID:25569606] "S. Typhimurium ST313 strains survived and replicated within different macrophages." Malawian sublineage 2.2 expresses SPI-2 constitutively even under non-inducing conditions [tool-summarized, PMID:38623411], i.e. the intracellular programme is pre-armed.
  5. Blunted innate inflammatory response, via reduced flagellin (GO:0044780) and consequently reduced inflammasome-driven IL-1β and pyroptosis (GO:0032731, GO:0070269), leads to failure of early containment and reduced macrophage death. [verbatim abstract, PMID:25569606] "Infection of macrophages with S. Typhimurium ST19 strains resulted in increased apoptosis and higher production of proinflammatory cytokines… compared to S. Typhimurium ST313 strains. This difference… could be explained, in part, by an increased production of flagellin by ST19 strains." Independent work confirms ST313 with "naturally attenuated flagellin elicits reduced inflammation and replicates within macrophages."
  6. Serum and antimicrobial-peptide resistance — increased pgtE expression results in degradation of host antimicrobial proteins and "increased resistance to complement deposition" (GO:0006956) [tool-summarized, PMID:30657108] — leads to survival in blood.
  7. Dissemination via infected mononuclear phagocytes to reticuloendothelial organs — spleen (UBERON:0002106), liver and Kupffer cells (UBERON:0002107, CL:0000091), bone marrow (UBERON:0002371), mesenteric lymph nodes (UBERON:0002509), gallbladder (UBERON:0002110) — results in systemic infection. Demonstrated in vivo: D23580 colonized "the spleen, mesenteric lymph nodes and gall bladder in mice… more rapidly… when compared to… SL1344" [verbatim abstract, PMID:26091096] (model organism).
  8. Sustained bacteraemia (UBERON:0000178) leads to the clinical syndrome: fever, hepatosplenomegaly, respiratory signs, anaemia (HP:0001945, HP:0001433, HP:0002789, HP:0001903).

Branch A — host control succeeds. Adequate IL-12→IFN-γ→STAT1 signalling (GO:0032735, GO:0032729, GO:0060333, GO:0071346) drives macrophage activation (GO:0042116) and Th1 responses (GO:0042088, CL:0000624, CL:0000623) resulting in bacterial clearance. [tool-summarized] "macrophages recognize the bacteria, activating T cells and NK cells through IL-12 and IL-23, and these activated cells release interferon-γ, which enhances macrophage activity via STAT1, aiding pathogen clearance."

Branch B — host control fails. This is the disease. Three non-exclusive routes: - B1, cellular: Mendelian IL-12/IFN-γ axis defect, or the STAT4 risk genotype with "reduced interferon-γ production in stimulated natural killer cells" and lower circulating IFN-γ during acute bacteraemia [tool-summarized, PMID:29523850], leads to failure of step B's macrophage activation. - B2, humoral (HIV): HIV infection leads to dysregulated anti-LPS antibody that inhibits serum bactericidal killing rather than mediating it [tool-summarized, PMID:20413503] — a gain of a harmful antibody specificity, not simply a loss. - B3, phagocyte-functional (malaria): haemolysis and haem oxygenase-1 induction are proposed to impair neutrophil oxidative burst (CL:0000775, GO:0006979, GO:0006879, CHEBI:18248), leading to permissiveness. Mechanistically attractive and not established in human iNTS; curate as a hypothesis with status: EMERGING.

Downstream branches from sustained bacteraemia: - → Septic shock: LPS-driven (CHEBI:16412, GO:0032496) cytokine response results in hypotension, lactataemia, DIC (HP:0002615, HP:0002151, HP:0005521). - → Meningeal seeding (UBERON:0002360, UBERON:0001359) results in meningitis with very high case fatality (HP:0001287). - → Endovascular seeding of atheromatous aorta or endocardium (UBERON:0000947, UBERON:0002165) results in mycotic aneurysm or endocarditis (HP:0100584). Predominantly in older adults. - → Osteoarticular seeding (UBERON:0001474, UBERON:0003657), strongly potentiated by sickle cell disease, results in osteomyelitis and septic arthritis (HP:0005661, HP:0003095). - → Persistence in gallbladder/reticuloendothelial niche with inadequate cell-penetrating therapy or uncorrected immunodeficiency results in recurrence (HP:0002718).

Category checklist coverage

  • Molecular pathways: IL-12/IL-23 → IFN-γ → JAK/STAT1 (KEGG hsa04630 JAK-STAT; hsa05132 Salmonella infection; Reactome interferon-γ signalling). Bacterial side: SPI-1 and SPI-2 type III secretion (GO:0030254), PhoPQ regulon, pgtE.
  • Cellular processes: phagocytosis (GO:0006909), intracellular replication, macrophage apoptosis (GO:0071888), pyroptosis (GO:0070269), neutrophil chemotaxis (GO:0030593), macrophage activation (GO:0042116).
  • Protein dysfunction: in the host, loss-of-function of IL-12Rβ1/IFNγR1/STAT1 (functional_impact_category: LOSS_OF_FUNCTION on the relevant genetic_context); in the pathogen, pseudogenization of flagellar and metabolic genes. Note for dismech: a pathogen-driven activity change with no host variant must use Descriptor.modifier, not functional_impact_category — the repository's Adult_T_Cell_Leukemia_Lymphoma precedent applies directly here.
  • Metabolic changes: ST313 shows altered melibiose and inositol utilization and differing Voges-Proskauer/catalase results versus SL1344 [verbatim abstract, PMID:26091096] — bacterial metabolic remodelling consistent with host restriction. No characterized host metabolomic signature.
  • Immune involvement: immunodeficiency-driven, not autoimmune. Both cellular (IFN-γ) and humoral (bactericidal antibody) arms are implicated, and their relative contribution is the field's stated open question: [verbatim abstract, PMID:30657108] "research efforts should focus on understanding the relative contributions of antibody and cell-mediated immunity to protection against iNTS disease in humans."
  • Tissue damage: reticuloendothelial hyperplasia, abscess formation, endovascular wall destruction in mycotic aneurysm, meningeal inflammation.
  • Molecular profiling: the substantial published profiling is bacterial transcriptomics (ST313 vs ST19 expression signatures; sublineage 2.2 signature, PMID:38623411) and bacterial genomics (PMID:37872141, PMID:40205197), not host omics. Host transcriptomic, proteomic, metabolomic and lipidomic signatures of iNTS disease are not established — search GEO/ArrayExpress at curation time rather than asserting any. The STAT4 eQTL work (PMID:29523850) is the closest thing to a host functional-genomics result.
  • Single-cell / spatial / CRISPR screens: no iNTS-specific published single-cell or spatial dataset was located. TraDIS (transposon-directed insertion-site sequencing) has been applied to S. Typhimurium in cattle, which is a bacterial functional-genomics screen and should be labelled as such.

7. Anatomical Structures Affected

Primary (always): blood UBERON:0000178.

Reticuloendothelial system (near-always, often subclinically): spleen UBERON:0002106; liver UBERON:0002107; bone marrow UBERON:0002371; mesenteric lymph nodes UBERON:0002509.

Portal of entry: small intestine UBERON:0002108, Peyer's patch UBERON:0001211, large intestine UBERON:0000059.

Secondary/metastatic sites: meninx UBERON:0002360 and cerebrospinal fluid UBERON:0001359; lung UBERON:0002048; gallbladder UBERON:0002110; aorta UBERON:0000947; endocardium UBERON:0002165; bone element UBERON:0001474; limb joint UBERON:0003657.

Body systems: cardiovascular (bacteraemia, endovascular), haematopoietic/reticuloendothelial, digestive, respiratory, nervous (meningitis), musculoskeletal.

Cell populations:

Cell type CL term Role
macrophage CL:0000235 primary replicative niche
monocyte CL:0000576 dissemination vehicle
Kupffer cell CL:0000091 hepatic reservoir
neutrophil CL:0000775 effector; impaired in malaria hypothesis
natural killer cell CL:0000623 early IFN-γ source; site of STAT4 effect
CD4-positive, alpha-beta T cell CL:0000624 Th1 macrophage activation
dendritic cell CL:0000451 antigen presentation / IL-12
intestinal epithelial cell CL:0002563 invasion (attenuated in ST313)
M cell of gut CL:0000682 translocation route
B cell / memory B cell CL:0000236 / CL:0000787 bactericidal antibody; vaccine target
erythrocyte CL:0000232 anaemia; haemolysis interface with malaria

Subcellular: Salmonella-containing vacuole (GO cellular-component binding should be searched at curation time rather than assumed); phagolysosome; cytosol for inflammasome assembly. Do not write a GO CC CURIE for the Salmonella-containing vacuole from memory — resolve it.

Localization/lateralization: systemic and bilateral by nature. Focal complications are typically unilateral and site-specific (a single aortic segment, one long bone, one joint) — lateralization carries no diagnostic meaning here.

8. Temporal Development

  • Onset: acute to subacute febrile illness developing over days. Not congenital. Age of occurrence is bimodal across settings: infants/toddlers in sub-Saharan Africa (peak "early in the second year of life" [PMID:40684736]), older adults elsewhere.
  • Stages: no formal staging system exists. A clinically useful progression is (i) uncomplicated bacteraemic febrile illness → (ii) bacteraemia with organ dysfunction (respiratory, anaemia, encephalopathy) → (iii) septic shock, or focal metastatic infection → (iv) death or recovery, with (v) recurrence as a distinct later state.
  • Progression rate: rapid. Untreated or inadequately treated disease progresses to death within days; meningitis and shock are the fastest routes.
  • Course pattern: acute and self-limited with treatment in immunocompetent hosts; relapsing/recurrent in uncontrolled HIV (20–40% recurrence pre-ART [PMID:22587967]); pooled recurrence 4.8% in the global meta-analysis [tool-summarized, PMID:35114140], a figure that reflects contemporary ART coverage.
  • Duration: days to weeks for an episode; chronic only in the sense of repeated episodes or an untreated endovascular/osteoarticular focus.
  • Remission: treatment-induced. Spontaneous resolution of true bacteraemia in a susceptible host should not be assumed.
  • Critical intervention windows: (a) first hours — prompt empiric therapy with an intracellularly active agent; (b) the whole episode — source control for endovascular foci, where [tool-summarized, PMID:35041743] "surgical intervention is indispensable in the management of Salmonella mycotic aneurysms"; (c) post-episode — ART initiation to prevent recurrence; (d) pre-exposure — infancy, the window a vaccine would target.

9. Inheritance and Population

Epidemiology

GBD 2017 [PMID:31562022, DOI:10.1016/S1473-3099(19)30418-9]:

Metric (2017) Estimate (95% UI)
Cases 535,000 (409,000–705,000)
Deaths 77,500 (46,400–123,000)
HIV-attributable deaths 18,400 (12,000–27,700) — 24.3% of total
DALYs 4.26 million (2.38–7.38 million)
Incidence, sub-Saharan Africa 34.5 per 100,000 person-years (26.6–45.0)
Incidence, all other regions <3.0 per 100,000 person-years
Incidence, <5 years 34.3 per 100,000 person-years (23.2–54.7)
Case fatality, all ages 14.5% (9.2–21.1)
Case fatality, ≥70 years 51.2% (30.2–72.9)
Case fatality, HIV-positive 41.8% (30.0–54.0)
Case fatality, HIV-negative 12.0% (7.3–18.0)

GBD 2021 [DOI:10.1371/journal.pntd.0012960, PLOS NTD, April 2025] [tool-summarized]: 509,976 incident cases (95% UI 413,361–606,167); 4,740,235 DALYs (2,762,282–7,597,208); age-standardized incidence 7.21 per 100,000 (5.83–8.64); Western sub-Saharan Africa highest burden (305,959 cases; ASR 47.54); low-SDI incidence 20.91 per 100,000; cases rose 1990–2005 then declined 2005–2021, with a net 45% increase in absolute cases driven chiefly by population growth.

Site-level trend, Blantyre, Malawi 2011–2019 [PMID:37153453] [tool-summarized]: minimum incidence fell from 21 to 7 per 100,000 per year; MDR in S. Typhimurium fell from 78.5% to 27.7% (via re-emergent chloramphenicol susceptibility); fluoroquinolone and third-generation cephalosporin resistance remained uncommon (1.3% and 1.1%); ESBL-producing Salmonella appeared in 2019.

Case fatality, pooled [verbatim abstract, PMID:35114140]: "the overall pooled CFR estimate was 14·7% (95% CI 12·2–17·3). When stratified by UN region, the pooled CFR was 17·1% (13·6–21·0) in Africa, 14·0% (9·4–19·4) in Asia, 9·9% (6·4–14·0) in Europe, and 9·6% (0·0–25·1) in the Americas."

Additional stratification [tool-summarized, PMID:35114140]: Southern Africa 33.1%, Western Africa 19.9%, Middle Africa 18.9%, Eastern Africa 15.8%; adults >15 y 21.0% vs children ≤15 y 12.0%; by serovar, Typhimurium 21.6%, Dublin 19.1%, Enteritidis 15.0%. HIV co-infection pooled OR for death 2.4 (95% CI 1.4–4.1).

An earlier Africa-specific systematic review covering 1966–2014 is available for regional incidence, risk factors and CFR [PMID:28056035, DOI:10.1371/journal.pntd.0005118].

Inheritance

Not a heritable disease. Inheritance pattern, penetrance, expressivity, anticipation, germline mosaicism, founder effects, consanguinity and carrier frequency are not applicable to iNTS disease itself. They apply only to the host susceptibility disorders in §4, where the MSMD-spectrum defects are variously autosomal recessive (IL12B, IL12RB1, complete IFNGR1/IFNGR2), autosomal dominant (partial IFNGR1, STAT1), or X-linked (IKBKG, CYBB). Do not populate an inheritance: block for this entry; record the susceptibility genes in genetic: with relationship_type: SUSCEPTIBILITY instead.

Population demographics

  • Geographic: overwhelmingly sub-Saharan Africa, with Western sub-Saharan Africa the highest-burden subregion. Secondary foci in South and Southeast Asia and East Asia (Taiwan, mainland China), where the adult/elderly endovascular phenotype predominates. Lowest burden Australasia.
  • Variant geography: ST313-L2 originated in DRC (~1980), spread to East Africa (~1995–2000) and West Africa (Ghana, 1994); sublineages 2.2 and 2.3 emerged in Malawi in 2006 and 2008 and now dominate there [PMID:37872141, PMID:38623411].
  • Age: infants and children <5 years in Africa; ≥55 years in high-income and East Asian series.
  • Sex ratio: reported as a significant risk factor in the global genomic census [PMID:40205197] but the direction and magnitude should be read from that paper; do not assert a ratio from this report.
  • Ethnicity: the burden distribution is driven by comorbidity prevalence and geography, not by ancestry per se. The one ancestry-linked genetic signal, STAT4 rs13390936, was identified in Kenyan and Malawian children; its frequency in other populations should be read from gnomAD.

10. Diagnostics

The one indispensable test

Blood culture. [tool-summarized, PMID:30657108] "bacterial culture of blood or cerebrospinal fluid is the only available method for diagnosis." This is the central diagnostic and health-systems problem: iNTS disease is undiagnosable clinically, and blood-culture capacity is scarce exactly where the disease is. The Marchello authors explicitly conclude [verbatim abstract, PMID:35114140] that "investments in improving clinical microbiology facilities to identify non-typhoidal salmonella… would prevent non-typhoidal salmonella invasive disease-associated illness and death."

Suggested terms: NCIT:C19347 Culturing, In Vitro Microbial; NCIT:C122437 Positive Blood Culture; NCIT:C173272 CSF Analysis. LOINC codes for blood culture and CSF culture should be looked up at curation time.

Supporting laboratory tests

Full blood count (anaemia, thrombocytopenia, leukocyte abnormalities), CRP/procalcitonin, lactate, glucose, renal and liver panels, blood film or rapid diagnostic test for malaria co-infection, HIV testing (mandatory in any adult with NTS bacteraemia, since it is AIDS-defining), CD4 count, sickle cell screening in children with osteomyelitis. Antimicrobial susceptibility testing is essential given the resistance landscape (§4).

Biomarkers

No validated iNTS-specific diagnostic or prognostic biomarker exists. No FDA-qualified biomarker is listed for this indication. Serology is not diagnostically useful — the MacLennan finding (high anti-LPS titres in the most susceptible hosts) shows why antibody titre cannot serve as a diagnostic marker here.

Imaging and functional studies

Imaging is used to find and characterize a focus, not to diagnose the infection: chest radiograph or CT for pneumonia and empyema; CT angiography for suspected mycotic aneurysm (essential in any older adult with NTS bacteraemia and back or abdominal pain); echocardiography for endocarditis; MRI for osteomyelitis and discitis; ultrasound or CT for splenic and hepatic abscess; CT/MRI brain in meningitis. Electrophysiology (EEG, EMG, ECG) has no primary diagnostic role; EEG may be used in encephalopathy or seizures.

Biopsy and pathology

Histopathology is rarely the diagnostic route. When tissue is obtained (aneurysm wall, bone, abscess), findings are non-specific acute suppurative inflammation with necrosis; culture of the tissue is the informative test. Reticuloendothelial hyperplasia may be seen at autopsy.

Genetic testing

Genetic testing is not part of diagnosing an iNTS episode. It is indicated to investigate the host when the clinical pattern suggests an inborn error: recurrent NTS invasive disease, NTS disease in an immunocompetent-appearing child, disseminated disease with an unusual serovar, or co-occurring mycobacterial or BCG disease. In that setting:

  • Targeted gene panel for MSMD / inborn errors of IL-12/IFN-γ immunity is the appropriate first-line test — consult the Genetic Testing Registry for current panels.
  • WES/WGS is appropriate when a panel is negative and clinical suspicion of an inborn error persists.
  • Single-gene testing is reasonable when a specific syndrome is suspected (e.g. CYBB for CGD with a suggestive dihydrorhodamine assay, or haemoglobin electrophoresis rather than sequencing for sickle cell disease).
  • Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing: not applicable. No copy-number, aneuploidy, mitochondrial, or repeat-expansion mechanism is implicated. Say so explicitly in the entry rather than leaving the fields ambiguous.
  • Functional immunology often precedes or complements sequencing: dihydrorhodamine/nitroblue-tetrazolium for CGD, IFN-γ/IL-12 pathway functional assays.

Omics-based diagnostics

Pathogen-side WGS is the mature omics application and is genuinely diagnostic-adjacent: it assigns sequence type and lineage, predicts resistance from gyrA/blaCTX-M/mphA genotype, and supports transmission inference [PMID:37872141, PMID:40205197]. Host-side RNA-seq, proteomics, metabolomics, epigenomics and liquid biopsy have no established diagnostic role for iNTS. Direct-from-blood molecular assays (multiplex PCR, metagenomic sequencing) are an active research direction for febrile-illness diagnosis in low-resource settings but are not standard of care for iNTS.

Clinical criteria and differential diagnosis

There is no consensus clinical case definition; the case definition is microbiological — isolation of a non-typhoidal Salmonella serovar from blood, CSF, or another normally sterile site. This is precisely how the meta-analysis defined inclusion [verbatim abstract, PMID:35114140]: "confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow)."

Differential diagnosis of the African febrile child or adult presenting this way:

Condition Distinguishing feature
Severe malaria Parasitaemia on film/RDT — but co-infection is common, so a positive malaria test does not exclude iNTS
Typhoid fever (S. Typhi) Clinically near-identical; separated only by serovar identification
Pneumococcal or other bacterial sepsis Blood culture
Bacterial meningitis (other organisms) CSF culture/PCR
Tuberculosis, disseminated Chronicity, imaging, mycobacterial testing; note MSMD hosts get both
HIV seroconversion / opportunistic infection HIV testing and CD4
Rickettsial and arboviral febrile illness Serology, exposure history, blood-culture-negativity
Brucellosis, leptospirosis, melioidosis Geography, exposure, targeted culture/serology

Screening

No screening programme exists or is recommended for iNTS, and none of newborn screening, carrier screening, or cascade screening applies. The closest analogues are (a) HIV testing as reflex screening in anyone with NTS bacteraemia, and (b) cascade family evaluation when an inborn error of IL-12/IFN-γ immunity is identified in an index case. Record both as such rather than as disease screening.

11. Outcome / Prognosis

Mortality

  • Pooled case fatality: 14.7% (95% CI 12.2–17.3) [PMID:35114140]; GBD 2017 estimate 14.5% [PMID:31562022]. The WHO consultation characterizes iNTS in sub-Saharan Africa as "associated with up to 20 % case-fatality ratio" [verbatim abstract, PMID:40132323].
  • Age gradient is steep: children ≤15 y 12.0%, adults >15 y 21.0% [PMID:35114140]; GBD puts ≥70 y at 51.2% [PMID:31562022].
  • HIV is the dominant prognostic comorbidity: CFR 41.8% HIV-positive vs 12.0% HIV-negative [PMID:31562022]; pooled OR for death 2.4 (1.4–4.1) [PMID:35114140].
  • Serovar matters: Typhimurium 21.6% > Dublin 19.1% > Enteritidis 15.0% [PMID:35114140].
  • Syndrome matters most: meningitis case fatality up to 50–70% in reviews, ~20% in African infants [PMID:35041743]; endocarditis "mortality is almost 50%, with or without cardiac surgery" [tool-summarized, PMID:35041743].

Survival is measured in 30-day or in-hospital terms, not 5- or 10-year terms. Do not populate 5-year or 10-year survival fields — they are not meaningful for an acute infection, and no such data exist. Life expectancy after recovery is governed by the underlying comorbidity (HIV stage, sickle cell disease), not by the iNTS episode.

Morbidity and function

Disability arises from (a) the acute episode's DALY burden — 4.26 million DALYs in 2017 [PMID:31562022], 4.74 million in 2021 [DOI:10.1371/journal.pntd.0012960] — dominated by years of life lost in young children rather than years lived with disability; (b) neurological sequelae of meningitis (hearing loss, epilepsy, developmental impairment) in survivors; (c) orthopaedic sequelae of osteomyelitis; (d) post-surgical morbidity after aneurysm repair. No iNTS-specific EQ-5D, SF-36, PROMIS, or ICF-coded outcome data were located. State this absence rather than borrowing a generic sepsis instrument.

Complications and recovery

See §3 for the complication table. Recovery is generally complete in immunocompetent survivors of uncomplicated bacteraemia treated promptly. Recovery potential is materially worse with (i) meningitis, (ii) endovascular focus without surgery, (iii) uncontrolled HIV, (iv) shock at presentation.

Prognostic factors

Established or strongly supported: HIV status and CD4 count; age (both extremes); shock at presentation; meningitis; endovascular focus; serovar; malnutrition; antimicrobial resistance of the isolate and consequent delay to effective therapy; malignancy. In the elderly Taiwanese cohort, independent predictors of 30-day mortality were solid-organ tumour (aOR 4.4), mycotic aneurysm (aOR 3.7), and shock (aOR 12.1) [tool-summarized, PMID:22261309].

Notably, malaria co-infection was not associated with increased mortality in the pooled analysis (OR 0.6, 95% CI 0.3–1.4) [tool-summarized, PMID:35114140] — malaria is a risk factor for acquiring iNTS disease but not, on this evidence, for dying of it. That distinction matters and is easy to get wrong.

No validated prognostic biomarker or prediction model exists for iNTS. Lactate, CRP and procalcitonin carry generic sepsis prognostic information only.

12. Treatment

Core principle

Effective agents must reach an intracellular pathogen. [tool-summarized, PMID:35041743] the agents with adequate intracellular penetration are "trimethoprim/sulfamethoxazole, fluoroquinolones, third generation cephalosporins, and azithromycin," and critically, [tool-summarized, PMID:35041743] "aminoglycosides should not be used even if the organisms are susceptible in vitro." That in-vitro-susceptible-but-clinically-ineffective gap is the single most important prescribing trap in this disease, and it has a mechanistic basis: gentamicin "lacks intracellular penetration" [tool-summarized, PMID:30657108].

Pharmacotherapy

Agent CHEBI Role dismech modelling note
Ceftriaxone CHEBI:29007 first-line empiric in Africa treatment_term NCIT:C15986 Pharmacotherapy + therapeutic_agent ceftriaxone; therapeutic_modality: SMALL_MOLECULE
Cefotaxime CHEBI:204928 alternative third-generation cephalosporin as above
Ciprofloxacin CHEBI:100241 targeted therapy for confirmed iNTS [tool-summarized, PMID:30657108] note reduced-susceptibility caveat below
Azithromycin CHEBI:2955 intracellularly active option mphA-mediated resistance emerging
Co-trimoxazole CHEBI:3770 (components CHEBI:45924, CHEBI:9332) historic therapy; now widely resisted; also HIV prophylaxis
Ampicillin CHEBI:28971 historic; MDR blaTEM
Chloramphenicol CHEBI:17698 historic; susceptibility re-emerged in Malawi
Meropenem CHEBI:43968 reserve for ESBL/XDR isolates
Dexamethasone CHEBI:41879 adjunct in bacterial meningitis per general guidelines evidence is not iNTS-specific — mark as such

Fluoroquinolone caveat [tool-summarized, PMID:35041743]: the reduced-breakpoint problem established for nalidixic-acid-resistant S. Typhi means "it is likely that the same issue pertains to treatment of iNTS infections." Read that as an explicit inference, not a demonstrated iNTS finding.

Duration is not standardized and should be taken from current guidelines at curation time, not from this report. The principle is that uncomplicated bacteraemia requires a substantially shorter course than an endovascular or osteoarticular focus, and that a focus requires prolonged therapy plus source control.

Pharmacogenomics

No CPIC guideline or FDA pharmacogenomic biomarker applies to iNTS therapy specifically. NAT2 and G6PD considerations for co-trimoxazole, and CYP3A4 interactions with azithromycin and antiretrovirals, are general rather than iNTS-specific. Check PharmGKB rather than asserting anything here.

Surgical and interventional

Source control is decisive for endovascular disease: [tool-summarized, PMID:35041743] "surgical intervention is indispensable in the management of Salmonella mycotic aneurysms." Also relevant: abscess drainage, empyema drainage, osteomyelitis debridement, prosthetic joint management (rare — "accounting for only 0.2% of PJI treated at the Mayo Clinic" [tool-summarized, PMID:35041743]), valve surgery in endocarditis. Suggested term NCIT:C15329 Surgical Procedure; therapeutic_modality: SURGERY.

Supportive, rehabilitative, and comorbidity-directed care

Fluid resuscitation (NCIT:C116537 Fluid Therapy), blood transfusion for severe anaemia (NCIT:C15192), oxygen and respiratory support, antimalarial treatment of co-infection, nutritional rehabilitation (NCIT:C15433 Nutritional Support), and — pivotally for recurrence prevention — antiretroviral therapy (NCIT:C94631 Antiretroviral Therapy). General supportive care NCIT:C15747. Rehabilitation is relevant to meningitis and osteomyelitis survivors (physiotherapy, audiology, developmental follow-up).

dismech binding caution. TreatmentTerm is rooted at NCIT:C25218 (Clinical Intervention or Procedure). Several terms above were resolved by label only and their enum reachability was not checked — NCIT:C116537 Fluid Therapy and NCIT:C122437 Positive Blood Culture in particular need just validate-terms before use. NCIT:C20496 Interferon Gamma and NCIT:C126712 Fluoroquinolone Antibiotic are substances/classes, not clinical actions, and belong in therapeutic_agent or qualifiers, never in treatment_term.term.

Advanced therapeutics

  • Gene therapy, cell therapy, RNA-based therapy, CAR-T, checkpoint inhibitors: not applicable to iNTS disease. Haematopoietic stem cell transplantation is relevant only as curative therapy for an underlying inborn error of IL-12/IFN-γ immunity, and should be curated on that entry rather than here.
  • Recombinant IFN-γ is used adjunctively in some patients with MSMD-spectrum defects and refractory intracellular infection. Evidence in iNTS specifically is case-level; curate with evidence_source: HUMAN_CLINICAL and directness: INDIRECT at best.
  • Monoclonal antibodies: a specific monoclonal antibody has been shown to overcome S. Typhimurium's intramacrophage survival mechanisms in vitro — a preclinical lead only.

Experimental treatments in trials

The active clinical development in this disease is preventive, not therapeutic (§13). No interventional therapeutic trial specific to iNTS disease was identified. One observational trial directly relevant to prevention is registered:

Field Value
Registration NCT07416461 (VINS)
Title Effectiveness of Malaria Vaccines in Reducing the Risk of Invasive Non-Typhoidal Salmonella Disease
Status Recruiting; actual start 2025-10-27
Design Observational, case-control (test-negative), prospective
Intervention studied R21/Matrix-M malaria vaccine
Primary outcome Blood-culture-confirmed iNTS disease in fully malaria-vaccinated vs unvaccinated children
Enrolment 10,000 (estimated)
Setting / sponsor Kisantu Health Zone, DRC / International Vaccine Institute

Curate this as phase: NOT_APPLICABLE (observational) and status: RECRUITING, and re-check the status before commit — the repository's just clinicaltrials-status-audit exists precisely because these drift.

Treatment strategy

Empiric therapy for severe febrile illness in an iNTS-endemic setting must cover NTS with a cell-penetrating agent, which in practice means a third-generation cephalosporin. On culture confirmation, narrow by susceptibility, extend duration for a focus, image for endovascular disease in older adults, treat malaria co-infection, test for HIV and start ART, and correct malnutrition and anaemia. There is no genotype-guided personalization of iNTS therapy; the one place host genotype changes management is when an inborn error of immunity is identified, which changes long-term prophylaxis and transplant candidacy rather than the acute regimen.

13. Prevention

Primary prevention

Comorbidity control is the intervention with demonstrated population effect. The Malawian decline — 21 to 7 per 100,000 per year between 2011 and 2019 [PMID:37153453] — occurred alongside reductions in malaria, HIV and acute malnutrition, and modelling attributes it to that combination rather than to any one factor [PMID:26230258]. Read this as strong quasi-experimental evidence that iNTS is controllable indirectly, and as the rationale for the VINS malaria-vaccine study above. Components: insecticide-treated nets and malaria chemoprevention, ART scale-up and prevention of vertical HIV transmission, nutrition programmes. NCIT:C15843 Preventive Intervention; NCIT:C16664 Health Education.

Immunization — the central prevention question

No licensed iNTS vaccine exists. [verbatim abstract, PMID:30657108] "No vaccine is currently available, making this a priority area for global health research." The pipeline has moved substantially since 2023, and this is the part of the entry most likely to be stale within a year.

Candidate Platform Stage / result Registration Citation
iNTS-GMMA (GSK GVGH) Bivalent generalized modules for membrane antigens (SEn + STm O-antigen) First-in-human phase 1, 31 healthy adults, 3 doses at 0/2/6 months. [tool-summarized] No serious or unexpected severe AEs; "All participants (19/19, 100%) in the iNTS-GMMA groups reported at least one solicited AEs, which were mostly mild to moderate in severity"; anti-O-antigen IgG and serum bactericidal antibody peaked at day 28 and persisted to day 350; supports advancement to phase I/II African trials EudraCT 2020-000510-14; ISRCTN51750695 PMID:40907249, eBioMedicine 2025, DOI:10.1016/j.ebiom.2025.105903
SALVO iNTS-GMMA in a European cohort Randomised placebo-controlled trial protocol published — PMID:37963701, BMJ Open 2023, DOI:10.1136/bmjopen-2023-072938
TSCV (trivalent Salmonella conjugate) Vi–tetanus-toxoid + core-plus-O-polysaccharide of STm and SEn conjugated to homologous FliC flagellin [verbatim abstract, PMID:41062830] "A total of 22 healthy adults aged 18-45 years were randomly allocated to 6.25-µg TSCV (n = 8), 12.5-µg TSCV (n = 10) or placebo (n = 4)… TSCV was safe and well tolerated… For each of the three polysaccharides, immune responses, as demonstrated by ≥4-fold increases over baseline, were observed among all (100%) vaccinees, and no responses were elicited in the placebo group" NCT03981952 PMID:41062830, Nature Medicine 2025, DOI:10.1038/s41591-025-04003-z
TSCV, phase 1/2a as above, dose-ranging in 80 US adults [tool-summarized] Well tolerated, no fevers; 85–100% response rates to all three polysaccharide antigens with no significant difference between doses NCT05525546 PMID:41885624, J Infect Dis 2026;233(6):1081–1090, DOI:10.1093/infdis/jiag156
iNTS-TCV (GVGH, trivalent with typhoid) GMMA + TCV combination Trial registered and ongoing NCT05480800 ClinicalTrials.gov

Regulatory and policy framing [verbatim abstract, PMID:40684736]: "A clinical development plan and regulatory pathway for licensure of iNTS vaccines has been shaped following the development of Preferred Product Characteristics and R&D Roadmap through a series of expert consultations. Several iNTS alone or combined with Typhoid Conjugate Vaccine platforms are in early clinical development. Encouraging safety and immunogenicity data have prompted developers and manufacturers to plan efficacy trials, aligned with regulatory expectations." The WHO expert consultation report [PMID:40132323] is the authoritative statement of the vaccine use case and Full Value of Vaccines Assessment framing.

Suggested term for the intervention class: NCIT:C15346 Vaccination; therapeutic_modality: VACCINE.

Secondary prevention

No screening programme for asymptomatic iNTS is recommended or plausible — there is no asymptomatic detectable state to screen for. Secondary prevention in practice means reducing time from fever to effective therapy, which is a diagnostic-capacity intervention (blood culture availability) rather than a screening one.

Tertiary prevention

Preventing recurrence and complications: ART initiation and adherence (the single most effective measure, given 20–40% pre-ART recurrence [PMID:22587967]); co-trimoxazole prophylaxis in HIV per national guidelines (NCIT:C51993 Antibiotic Prophylaxis — note this reduces a range of infections and is not iNTS-specific); source control for endovascular and osteoarticular foci; nutritional rehabilitation; pneumococcal and other routine immunization in sickle cell disease.

Genetic counselling

Applies only to identified inborn errors of IL-12/IFN-γ immunity and to sickle cell disease, where standard counselling, carrier testing and prenatal options apply to those conditions. There is no genetic counselling, carrier screening, PGD, or prenatal testing for iNTS disease. Do not create a treatments: entry for genetic counselling on this disease entry.

Public health and environmental interventions

Water, sanitation and hygiene; food safety along the poultry, egg, dairy and meat chain; hand hygiene; health education. The honest caveat is that the evidence base for WASH and food-safety impact on African iNTS specifically is thin, because the reservoir is unresolved (§5). If transmission is predominantly person-to-person within households, as the recent genomic evidence suggests [PMID:36910696, PMID:40205197], then food-chain interventions designed for zoonotic NTS may have limited effect on iNTS, and household-level hygiene and case-contact measures matter more. This is a live policy-relevant uncertainty and should be curated as such.

14. Other Species / Natural Disease

Taxonomy of affected hosts

Species NCBITaxon Relevance
Homo sapiens NCBITaxon:9606 the disease entry's host
Bos taurus look up at curation time S. Dublin host-adapted reservoir
Mus musculus NCBITaxon:10090 primary experimental model
Gallus gallus NCBITaxon:9031 experimental model; poultry reservoir for NTS generally
Macaca mulatta NCBITaxon:9544 non-human primate work exists for Salmonella generally

Natural disease in other species

The clearest natural counterpart is bovine salmonellosis due to S. Dublin, a host-adapted invasive serovar. [tool-summarized] S. Dublin "is a bovine-adapted zoonotic pathogen, capable of causing invasive disease in both cattle and human hosts"; it is "the most common serovar isolated from clinical case submissions" in cattle, has "become substantially more prevalent in dairy and calf-rearing facilities in the US and Canada since 2012," and in calves "infections are invasive, leading to high rates of septicemia, respiratory disease, and death." Transmission is "primarily fecal-oral, cattle-to-cattle and cattle-to-human transmission may also occur via contaminated saliva or milk," and the organism is multi-drug resistant.

This matters for the human entry in two ways: S. Dublin has the third-highest serovar-specific human iNTS case fatality (19.1% [PMID:35114140]), and it is the one invasive serovar with an unambiguous animal reservoir — the counterexample that makes the African ST313 host-restriction argument sharper.

Non-typhoidal salmonellosis also occurs naturally in horses, pigs, poultry, reptiles (a well-known source of human paediatric infection), companion animals, and wildlife. OMIA is the resource for any heritable animal susceptibility trait; none is established as a counterpart to human MSMD for this purpose.

Comparative biology and evolutionary conservation

The mechanistically interesting comparison is convergent host restriction: ST313 is undergoing genome degradation that parallels S. Typhi and S. Paratyphi A [verbatim abstract, PMID:25569606], and independently parallels the host adaptation of S. Dublin (cattle) and S. Gallinarum (poultry). Pseudogene accumulation, reduced flagellar expression, and loss of broad-host-range metabolic capacity recur across these lineages. The host-side IL-12/IFN-γ axis is deeply conserved, which is what makes the mouse model informative at all — IFN-γ-axis knockouts in mice reproduce the human susceptibility phenotype in kind.

Zoonotic potential and cross-species susceptibility

Non-typhoidal Salmonella as a genus is strongly zoonotic. The specific African iNTS pathovars appear to be losing that character, which is the crux of §5. Cross-species experimental susceptibility is demonstrated: D23580 (ST313) "is able to establish an invasive infection in chickens" [verbatim abstract, PMID:26091096], so ST313 is not host-restricted in the strict experimental sense even if it is epidemiologically anthroponotic. Both facts should appear in the entry; quoting only one misrepresents the field.

15. Model Organisms

Murine models

Oral-challenge BALB/c model of ST313 [verbatim abstract, PMID:26091096]: "we report that D23580 causes lethal and invasive disease in a murine model of infection following peroral challenge. The LD50 of D23580 in female BALB/c mice was 4.7 x 10⁵ CFU. Tissue distribution studies performed 3 and 5 days post-infection confirmed that D23580 was able to more rapidly colonize the spleen, mesenteric lymph nodes and gall bladder in mice when compared to the well-characterized S. Typhimurium strain SL1344." The authors state this is "the first full duration infection study using an ST313 strain following the entire natural course of disease progression."

For a dismech animal_models[] entry:

species: Mouse
genotype: BALB/c (Nramp1/Slc11a1-susceptible), wild-type host
name: BALB/c peroral D23580 (ST313) challenge model
publication: PMID:26091096
modeled_mechanisms:
  - target: <dissemination-to-reticuloendothelial-organs node>
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      BALB/c mice carry a susceptible Slc11a1 allele, so the model's
      permissiveness derives from a murine genetic defect with no counterpart
      in the human risk factors (HIV, malaria, malnutrition) that define iNTS
      disease. The model reproduces invasive dissemination but not the
      comorbidity gating that is the disease's defining epidemiological feature.

Key limitation to state explicitly: the standard mouse typhoid model achieves invasiveness through Slc11a1 (Nramp1) susceptibility and an artificially high inoculum, not through the immunodeficiency states that permit human iNTS disease. A HUMAN_MODEL_MISMATCH discussion is the right structure for this, not a generic KNOWLEDGE_GAP — the model exists and works, and the open question is its translational validity to the comorbidity-gated human disease.

Cellular and in vitro models

The macrophage-infection system is where the ST313 phenotype was defined [PMID:25569606], using J774 murine macrophages, THP-1 cells, U937 monocytes, HEK293-Luc reporter cells, primary peritoneal macrophages from BALB/c and CD-1 mice, and human PBMCs. Reported quantitative readouts [tool-summarized]: ST313 intracellular survival 160% ± 26% in THP-1 at 24 h versus 47% ± 3% for ST19; motility zone 17 ± 3 mm (ST313) versus 24 ± 2 mm (ST19), P<0.001; lower IL-1β and TNF-α at 3 and 8 h.

For dismech, these are experimental_models: entries (non-animal systems) with modeled_mechanisms linking to the intramacrophage-replication and blunted-inflammation nodes, model_scale: CELLULAR, and readouts carrying the survival percentages and motility measurements above. Note that linking a CELLULAR-scale model to a TISSUE- or ORGANISM-scale node is upward extrapolation and requires limitations under check_upward_extrapolating_links_are_caveated.

Avian model

D23580 establishes invasive infection in experimentally infected chickens, demonstrating that ST313 is "not host-restricted" in an experimental sense. Useful specifically for testing the host-restriction hypothesis; species: Chicken, NCBITaxon:9031, relationship: PARTIALLY_RECAPITULATES at best, since the avian immune context differs substantially.

Genetic models available

Mouse knockouts across the relevant axis are standard and well-characterized: Ifng, Ifngr1, Ifngr2, Il12b, Il12rb1, Stat1, Stat4, Slc11a1 congenics, Cybb (CGD model). Conditional and humanized options exist. Consult MGI, IMPC, KOMP and IMSR for current allele availability rather than asserting a specific allele here. A Stat4 model is the obvious direct test of the human GWAS finding and would close a real evidential gap — the human result is genetic and eQTL-based, and an in vivo challenge experiment in a Stat4-hypomorphic host would be the corresponding Experiment with would_support: pathophysiology#<IFN-γ axis failure node>.

Bacterial genetic resources

Not "model organisms" in the usual sense but central to this disease's experimental literature: D23580 is the reference ST313 L2 isolate with an annotated, functionally characterized genome; SL1344 and ATCC 14028 are the ST19 comparators; A130 is a second ST313 strain. Transposon-directed insertion-site sequencing has been applied to S. Typhimurium in a bovine niche.

What the models do not capture

  1. Comorbidity gating — no model reproduces the HIV/malaria/malnutrition context that defines human iNTS.
  2. Dysregulated inhibitory anti-LPS antibody — the MacLennan mechanism [PMID:20413503] is a human HIV-specific phenomenon with no animal counterpart.
  3. Transmission — if iNTS is person-to-person [PMID:40205197], no animal model can test the transmission route.
  4. Human-specific IFN-γ axis variants — mouse orthologs are conserved but the specific human hypomorphic alleles and the STAT4 eQTL effect are not modelled.

Cross-cutting notes for the dismech entry

  1. Genetics slots: populate genetic: with relationship_type: SUSCEPTIBILITY only. There is no causal gene, no inheritance block, no chromosomal abnormality, no host epigenetics. Say so explicitly in notes: rather than leaving the sections silently empty.
  2. Pathogen activity states use modifier, not functional_impact_category. ST313's constitutive SPI-2 expression and blunted flagellin output are bacterial states with no host variant to describe — the same rule the repository applies to HTLV-1 Tax in Adult_T_Cell_Leukemia_Lymphoma.
  3. Prevalence records: GBD figures are measure_type: ANNUAL_INCIDENCE with rate_denominator: PERSON_YEARS (the GBD figures are per 100,000 person-years, and that denominator has no fallback). The Blantyre figures are minimum incidence estimates and should carry that caveat in notes:.
  4. Two case-fatality figures will both look right: 14.5% (GBD 2017 modelled) and 14.7% (Marchello pooled, hospital-based). They are different measurements, not a discrepancy; record both with their measure and source rather than picking one.
  5. Candidate mechanism modules to check before creating anything new: run just list-modules and look for existing sepsis/bacteraemia, intracellular pathogen persistence, granuloma/abscess, and immunodeficiency modules. intracellular_pathogen_persistence is named in CLAUDE.md as a gating module for antimicrobial work and is a strong conforms_to candidate for the intramacrophage-replication node.
  6. Coarse phenotype bindings are expected here and are not a defect. HP:0001945 Fever on a disease whose presentation is "fever alone" is SOURCE_UNSPECIFIED or VARIABLE_SPECTRUM, not a curation failure — see the coarse-phenotype-bindings skill.
  7. Every number and quotation above needs a cache file before it becomes evidence. Fetch each PMID with just fetch-reference, then just count-verified-snippets in the loop and just validate-disorders once before the PR.

Reference list

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29523850 10.1038/s41467-017-02398-z Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4. Nat Commun 2018
26109132 10.1038/nri3858 Gilchrist JJ, MacLennan CA, Hill AVS. Genetic susceptibility to invasive Salmonella disease. Nat Rev Immunol 2015
20413503 10.1126/science.1180346 MacLennan CA et al. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science 2010
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26230258 10.1371/journal.pntd.0003979 Modelling the contributions of malaria, HIV, malnutrition and rainfall to the decline in paediatric iNTS disease in Malawi. PLoS Negl Trop Dis 2015
28056035 10.1371/journal.pntd.0005118 Uche IV et al. A systematic review of the incidence, risk factors and case fatality rates of invasive nontyphoidal Salmonella (iNTS) disease in Africa (1966–2014). PLoS Negl Trop Dis 2017
36910696 10.1093/ofid/ofad086 Chirwa EB, Dale H, Gordon MA, Ashton PM. What is the source of infections causing invasive nontyphoidal Salmonella disease? Open Forum Infect Dis 2023
40205197 10.1038/s41591-025-03644-4 Genomic census of invasive nontyphoidal Salmonella infections reveals global and local human-to-human transmission. Nat Med 2025
40907249 10.1016/j.ebiom.2025.105903 Safety and immunogenicity of the iNTS-GMMA vaccine: a first-in-human, randomised, dose escalation trial. eBioMedicine 2025
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— 10.1371/journal.pntd.0012960 The global, regional, and national burden of invasive non-typhoidal Salmonella: GBD 1990–2021. PLoS Negl Trop Dis 2025
— NCT07416461 VINS: Effectiveness of malaria vaccines in reducing the risk of iNTS disease (recruiting, 2025)

Sources: GBD 2017 iNTS burden · Marchello complications and mortality meta-analysis · EcoSal Plus iNTS in Africa · Feasey Lancet 2012 · Genomic appraisal of invasive S. Typhimurium · ST313 sublineage 2.2 in Malawi · ST313 macrophage phenotype · D23580 murine model · STAT4 GWAS · CID iNTS infections review · Blantyre incidence 2011–2019 · Source of iNTS infections · Nature Medicine genomic census · iNTS-GMMA phase 1 · Trivalent Salmonella conjugate vaccine phase 1/2a · WHO iNTS vaccine landscape analysis · GBD 1990–2021 iNTS · MacLennan Science 2010 · Elderly NTS bacteraemia · VINS trial NCT07416461 · MONDO:0017944 via NORD · Salmonella Dublin in cattle