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)

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 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.

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:

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

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):

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."

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

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:

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]:

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:

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

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:

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.

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

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

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