Verruga Peruana (Peruvian Wart) — Comprehensive Disease Characterization Report

Disease: Verruga Peruana (chronic eruptive phase of Carrión's disease) MONDO ID: MONDO:0971058 Category: Infectious Disease (neglected tropical, vector-borne, bacterial) Investigation: 5 iterations · 16 confirmed findings · 71 papers reviewed Evidence base: Aggregated disease-level literature (reviews, clinical series, meta-analysis, in vitro/molecular studies). No individual-patient (EHR) data or primary datasets were provided.

Summary

Verruga Peruana ("Peruvian wart") is the chronic, eruptive tissue phase of Carrión's disease, a biphasic bacterial infection caused by the sand fly–transmitted α-proteobacterium Bartonella bacilliformis (rarely B. ancashensis or B. rochalimae). It is endemic to the Andean valleys of Peru, Ecuador, and Colombia (typically 500–3,200 m elevation), where an estimated 1.7 million people are at risk. The disease is purely infectious and vector-borne: there is no human genetic etiology, no causal gene, and no inheritance pattern. The relevant genetics belong entirely to the pathogen.

The core biology is best summarized as one pathogen with two tropisms. After inoculation by a Lutzomyia/Pintomyia sand fly, B. bacilliformis pursues two distinct cellular targets. In the acute phase (Oroya fever), it invades and lyses circulating erythrocytes — up to 100% parasitized and 80% lysed — producing severe, often-fatal hemolytic anemia. In the chronic eruptive phase (verruga peruana), tropism shifts to dermal vascular endothelial cells, where the bacterium drives pathological angiogenesis to produce crops of bleeding, angioproliferative skin nodules. The autotransporter BafA promotes endothelial proliferation via VEGF-receptor signaling, while an immunosuppressive, TH1-downregulated, pro-angiogenic (IL-10-high) cytokine milieu facilitates persistence.

Clinically, the two phases diverge sharply in prognosis and treatment. Untreated Oroya fever carries high mortality; the eruptive verruga phase is rarely fatal and its nodules regress once the bacterial stimulus is cleared. Treatment is phase-specific — ciprofloxacin (or chloramphenicol + penicillin G) for the acute phase, and rifampin or azithromycin for the eruptive phase. Prevention relies on sand fly vector control and early case detection; there is no licensed vaccine, only preclinical in silico multi-epitope candidates. Diagnosis rests on peripheral blood smear/culture (acute) and skin biopsy with Warthin-Starry silver staining (eruptive), supported by PCR and serology. The disease remains neglected: asymptomatic carriers sustain transmission, diagnostics miss low-bacteremia carriers, and antibiotic-resistant strains are emerging.

Key Findings

F001 — Verruga Peruana is the chronic eruptive phase of Carrión's disease

Verruga peruana is the tissue/eruptive phase of the biphasic Carrión's disease, caused by Bartonella bacilliformis, a motile, flagellated, Gram-negative intracellular α-proteobacterium. The eruptive phase is characterized by eruptive nodules that commonly bleed, plus arthralgias, with currently very low mortality — in stark contrast to the acute Oroya fever phase. A second causal agent, Bartonella ancashensis, was isolated from Verruga Peruana patients in the rural Ancash region of Peru.

"produces in its tissue phase a characteristic dermal eruption (Verruga peruana) resulting from a pronounced endothelial cell proliferation" — PMID: 1693472

"The eruptive phase, also known as Peruvian Wart, is characterized by eruptive nodes (which commonly bleed) and arthralgias. The mortality of the eruptive phase is currently extremely low." — PMID: 15798808

"Bartonella ancashensis, which was isolated in blood samples from 2 patients living in Caraz, Peru, during a clinical trial of treatment for bartonellosis" — PMID: 28221130

Synonyms / alternative names: Peruvian wart, Verruga peruana, eruptive-phase bartonellosis, chronic-phase Carrión's disease. Identifiers: MONDO:0971058; MeSH "Bartonella bacilliformis"/"Bartonella Infections"; ICD-10 A44.1 (cutaneous/mucocutaneous bartonellosis), A44.0 (systemic/Oroya fever); ICD-11 1C11.1. This is an aggregated disease-level characterization (not derived from individual EHR patients).

F002 — Pathological angiogenesis via VEGF-receptor signaling (BafA)

Verruga formation results from B. bacilliformis-driven endothelial cell proliferation and pathological angiogenesis. Bacterial extracts stimulate human endothelial cell proliferation up to three times control and induce new blood-vessel formation in vivo. The autotransporter BafA passenger domain promotes endothelial angiogenesis via VEGF-receptor signaling. Histologically, bacteria reside in the interstitium and within endothelial cytoplasm (Rocha-Lima inclusions).

"B. bacilliformis possess an activity that stimulates endothelial cell proliferation up to three times that of control" — PMID: 1693472

"B. bacilliformis extracts stimulate the formation of new blood vessels in an in vivo model for angiogenesis" — PMID: 1693472

"Bartonella bacilliformis is a Gram-negative bacterial pathogen that provokes pathological angiogenesis and causes Carrion's disease, a neglected tropical disease restricted to South America" — PMID: 35379004

Ontology suggestions: GO:0001525 (angiogenesis), GO:0001938 (positive regulation of endothelial cell proliferation), GO:0048010 (VEGF receptor signaling pathway); CL:0000115 (endothelial cell); protein: BafA autotransporter.

F003 — Sand fly transmission; endemic Andean valleys; ~1.7 million at risk

Transmission is by phlebotomine sand flies (Lutzomyia verrucarum and related Pintomyia/Lutzomyia spp.). B. bacilliformis DNA has been detected in Pintomyia robusta at the Ecuador–Peru border. The disease is endemic to Andean regions of Peru, Ecuador, and Colombia at 500–3,200 m; ~1.7 million South Americans are estimated at risk. Seroprevalence of 28% among healthy children in rural Loja Province, Ecuador, indicates widespread unrecognized infection.

"This infection is endemic of Andean regions and it is estimated that approximately 1.7 million of South Americans are at risk." — PMID: 26824740

"Seroprevalence of 28% was found among children in the study communities." — PMID: 29941982

Ontology suggestions: UBERON:0002097 (skin of body); vector taxa Lutzomyia verrucarum, Pintomyia robusta.

F004 — Acute-phase hemolysis via porin A and an α/β-hydrolase

The acute phase (Oroya fever) is characterized by fatal hemolytic anemia. A Tn5 transposon screen identified porin A and an α/β-hydrolase as both necessary and sufficient for B. bacilliformis-induced hemolysis; the α/β-hydrolase catalytic triad (Ser205, Asp267, His310) is essential, and compound 48/80 inhibits hemolysis in the micromolar range. The bacterium invades and parasitizes erythrocytes, producing intracellular bacilli visible on blood smear.

"we determine that porin A and α/β-hydrolase are both necessary and sufficient for hemolysis induced by B. bacilliformis" — PMID: 41315277

"Carrion's disease is endemic to the South American Andes and is characterized by fatal hemolytic anemia." — PMID: 41315277

F005 — Phase-specific treatment

Nationally standardized treatment for the acute phase in Peru is ciprofloxacin, with chloramphenicol plus penicillin G as an alternative. For the eruptive (verruga peruana) phase the recommended treatment is rifampin (azithromycin is also used). Emergence of antibiotic-resistant strains motivates anti-virulence and novel drug-target discovery efforts.

"There are nationally standardized treatments for the acute phase, which consist of ciprofloxacin, and alternatively chloramphenicol plus penicillin G." — PMID: 15798808

"During the eruptive phase the recommended treatment is rifampin" — PMID: 15798808

"the emergence of antibiotic-resistant strains underscores the urgent need for novel therapeutic interventions" — PMID: 41792177

Ontology suggestions (NCIT): Rifampin, Azithromycin, Ciprofloxacin, Chloramphenicol, Penicillin G.

F006 — Clinical phenotype

The eruptive verruga phase presents with crops of red-purple angiomatous papules/nodules on skin (face, trunk, extremities) that commonly bleed and can ulcerate, accompanied by arthralgias and malaise. Peruvian wart may be clinically indistinguishable from bacillary angiomatosis. The preceding acute Oroya fever phase presents with fever, anorexia, malaise, nausea/vomiting, pallor, hepatomegaly, lymphadenopathy, cardiac murmur, jaundice, arthralgias, and severe hemolytic anemia. In pediatric outbreaks, children are the most affected group.

"Peruvian wart, caused by B. bacilliformis, may be indistinguishable from bacillary angiomatosis caused by the other two species." — PMID: 31780437

"In the pediatric population, the acute phase symptoms are fever, anorexia, malaise, nausea and/or vomiting. The main signs are pallor, hepatomegaly, lymphadenopathies, cardiac murmur, and jaundice." — PMID: 15798808

Suggested HPO terms: HP:0000988 (skin nodule), HP:0011276 (vascular skin abnormality), HP:0002829 (arthralgia), HP:0001945 (fever), HP:0001878 (hemolytic anemia — acute phase), HP:0002240 (hepatomegaly), HP:0002716 (lymphadenopathy), HP:0000952 (jaundice).

F007 — Diagnosis and differential

Acute-phase diagnosis relies on Giemsa-stained peripheral blood smear (intraerythrocytic bacilli) and blood culture; eruptive-phase diagnosis rests on skin biopsy showing vascular proliferation with prominent endothelium and Bartonella aggregates, demonstrable by Warthin-Starry silver stain. Serology and PCR (16S-23S ITS, gltA, MLST) confirm. The angioproliferative nodules resemble bacillary angiomatosis, Kaposi sarcoma, pyogenic granuloma, and epithelioid hemangioma — the differential diagnosis.

"vessels with prominent endothelium and stroma rich in leukocytoclastic polymorphonuclears" — PMID: 12152480

"Histopathologically, BA may be confused with angiosarcoma, pyogenic granuloma and epithelioid hemangioma." — PMID: 10718405

"This bacterium is a fastidious slow growing microorganism, which is difficult and cumbersome to isolate from clinical sources" — PMID: 26824740

F008 — Purely infectious etiology; no human genetics

Verruga Peruana / Carrión's disease is caused by infection with B. bacilliformis (rarely B. ancashensis or B. rochalimae), transmitted by phlebotomine sand flies. There is no Mendelian inheritance, no human causal gene, no pathogenic germline/somatic variant, and no chromosomal abnormality; OMIM has no gene entry. The relevant genetics are the pathogen's virulence genes: bafA (autotransporter), porin A, α/β-hydrolase, flagellin flaA, and the ialB invasion locus. B. ancashensis uniquely carries a type IV secretion system absent from B. bacilliformis.

"B. ancashensis contains type IV secretion system proteins, which are not present in B. bacilliformis" — PMID: 28221130

Implication: Sections on causal genes, pathogenic variants, modifier genes, epigenetics, chromosomal abnormalities, inheritance patterns, penetrance, carrier frequency, and genetic screening are not applicable to this disease as a host trait.

F009 — Immunosuppressive, TH1-downregulated, pro-angiogenic cytokine profile

In 144 healthy Peruvian subjects from endemic/post-outbreak villages, bacteremia was associated with low concentrations of TH1/pro-inflammatory mediators: HGF (p=0.005), IL-15 (p=0.002), IL-6 (p=0.05), IP-10/CXCL10 (p=0.008), MIG/CXCL9 (p=0.03), and MIP-1α/CCL3 (p=0.03). Angiogenic chemokines and IL-10 were positively associated with infection. Recent acute infection (IgM+) showed lower eotaxin, IL-6, and VEGF but higher GM-CSF and IL-10.

"the same and further TH1-related and pro-inflammatory biomarkers were inversely associated with infection, whereas angiogenic chemokines and IL-10 were positively associated" — PMID: 28628613

"The presence of bacteremia was associated with low concentrations of HGF (p = 0.005), IL-15 (p = 0.002), IL-6 (p = 0.05), IP-10 (p = 0.008), MIG (p = 0.03) and MIP-1α (p = 0.03)" — PMID: 28628613

Interpretation: Immune evasion (TH1 suppression) and a pro-angiogenic/IL-10-high milieu together support bacterial persistence and feed the angioproliferative phenotype — immune modulation and angiogenesis are mechanistically coupled.

F010 — Epidemiology and asymptomatic reservoir

A 2025 systematic review/meta-analysis (5 studies, 717 individuals, Peru & Ecuador) found IgG seropositivity of 28.21% (95% CI 6.29–33.39) in healthy Ecuadorian children and a pooled molecular detection rate of 15.60% (95% CI 4.24–31.98) in symptomatic Peruvian individuals. A gradual reduction in infection rates among acute febrile patients in Peru was observed. Asymptomatic carriers act as a human reservoir, and current PCR tools poorly detect low-bacteremia carriers.

"The percentage of seropositive IgG antibodies against B. bacilliformis was 28.21% (95% CI: 6.29-33.39) among healthy Ecuadorian children. In Peru, the pooled bacterial detection rate in symptomatic individuals was 15.60% (95% CI: 4.24-31.98)" — PMID: 40037746

"misdiagnosis, wrong treatments and perpetuation of asymptomatic carriers living in endemic areas" — PMID: 26959642

F011 — Phase-dependent prognosis

Untreated acute-phase Carrión's disease (Oroya fever) has high mortality, driven by severe hemolytic anemia and superimposed infections (e.g., Salmonella) plus cardiovascular/neurologic complications. In contrast, mortality of the eruptive (verruga peruana) phase is extremely low, and the angioproliferative nodules regress once the bacterial stimulus is cleared. Antibiotic-resistant strains have been reported, and there is no vaccine.

"responsible for the Carrion's disease widely distributed in Ecuador, Peru, and Colombia with a high mortality rate when no specific treatment is received" — PMID: 32931955

"The mortality of the eruptive phase is currently extremely low." — PMID: 15798808

F012 — Prevention: vector control; no vaccine

There is no available vaccine. Prevention is based on vector control against phlebotomine sand flies — insecticide spraying, insecticide-treated bed nets, protective clothing/repellents, and avoiding dusk-dawn exposure — plus early case detection and treatment to reduce the human reservoir. Multi-epitope subunit vaccine candidates (targeting flagellar biosynthetic protein, Pap31, heme/hemin transporters) have been designed by immunoinformatics but remain preclinical/in silico.

"Currently there is no available vaccine against B. bacilliformis. While antibiotics are the standard treatment, resistant strains have been reported, and there is a potential spread of the vector that transmits the bacteria." — PMID: 39566279

"B bacilliformis is transmitted by Sand fly (Lutzomyia verrucarum) to healthy individuals" — PMID: 32931955

F013 — Erythrocyte tropism: adhesins bind spectrin, band 3, glycophorin A

During the acute phase, up to 100% of circulating erythrocytes can be parasitized and 80% lysed. B. bacilliformis binds multiple surface erythrocyte proteins: spectrin (α/β, 230/210 kDa), band 3 (100 kDa), and glycophorin A (83 kDa), dependent on carbohydrate moieties. Invasion is mediated by invasion-associated loci ialA/ialB; ialB is induced by lower temperature (20°C) and acidic pH — cues signaling sandfly-to-host transmission — and repressed at 37°C. B. bacilliformis is the sole ancestral-lineage Bartonella, lacks the VirB/VirD4 T4SS, and the modern lineage uses the Trw T4SS pilus for erythrocyte invasion.

"During the primary disease phase, up to 100% of the circulating erythrocytes can be parasitized and 80% lysed. During the secondary phase of this disease, bacterial invasion shifts to endothelial cells lining the vasculature." — PMID: 12668141

"the 230 and 210 kDa proteins are the alpha and beta subunits of spectrin; the 100 and 83 kDa proteins are band 3 protein and glycophorin A" — PMID: 10968948

"Trw, is present in a sub-branch of the modern lineage. Trw does not translocate any known effectors, but produces multiple variant pilus subunits critically involved in the invasion of erythrocytes" — PMID: 18489724

Ontology suggestions: CL:0000232 (erythrocyte); GO:0007155 (cell adhesion); UBERON:0000178 (blood).

F014 — Endothelial invasion requires tyrosine phosphorylation and α5β1 integrin

In the secondary (tissue) phase, invasion shifts to endothelial cells. Invasion of human endothelial (HUVEC) and epithelial (HEp-2) cells is reduced by protein kinase inhibitors genistein (tyrosine kinase) and staurosporine (PKC/tyrosine kinase) dose-dependently. Infection induces host tyrosine phosphorylation of multiple proteins (110–243 kDa), and anti-α5 and anti-β1 integrin antibodies moderately decrease uptake, implicating α5β1 integrin in bacterial entry into nucleated cells.

"exposure of normal human umbilical vein endothelial cells to staurosporine, a potent inhibitor of protein kinase C and some tyrosine protein kinases, resulted in a considerable reduction in the number of organisms internalized" — PMID: 10077844

"anti-alpha 5 and anti-beta 1 chain integrin monoclonal antibodies resulted in a moderate decrease in the invasion of these cells, suggesting a possible role of alpha 5 beta 1 integrins in the uptake" — PMID: 10077844

Ontology suggestions: GO:0007169 (transmembrane receptor protein tyrosine kinase signaling), GO:0007229 (integrin-mediated signaling pathway); protein: ITGA5/ITGB1 (α5β1 integrin).

F015 — Anatomical involvement and model systems

Primary anatomical targets: circulating erythrocytes/blood (acute) and dermal vascular endothelium/skin (eruptive). Secondary organ involvement in severe acute disease includes liver (hepatomegaly), spleen (splenomegaly), lymph nodes (lymphadenopathy), heart (murmur/myocarditis), and CNS (neurobartonellosis). Model systems are cellular/in vitro (HUVEC, HEp-2, human erythrocyte-binding assays) and entomological (experimental colonization of Lutzomyia sand flies). Humans (Homo sapiens, NCBI Taxon 9606) are the sole known reservoir; there is no established natural non-human animal disease, though historically experimental infection of non-human primates (rhesus macaque) was used.

"B. bacilliformis is transferred between human hosts by the sandfly, Lutzomyia verrucarum" — PMID: 12668141

"colonize endothelial cells and erythrocytes of their mammalian reservoir hosts, thereby causing long-lasting intraerythrocytic infections" — PMID: 18489724

Ontology suggestions: UBERON:0002097 (skin), UBERON:0000178 (blood), UBERON:0001981 (blood vessel), UBERON:0002107 (liver), UBERON:0002106 (spleen); CL:0000115 (endothelial cell), CL:0000232 (erythrocyte).

F016 — Integrated model: one pathogen, two tropisms

Synthesis of all findings: sand fly inoculation of B. bacilliformis → Branch A (IalA/IalB + flagella-mediated erythrocyte invasion via spectrin/band 3/glycophorin A; porin A/α-β-hydrolase hemolysis) → severe hemolytic anemia (Oroya fever, high untreated mortality); → Branch B (α5β1-integrin/tyrosine-kinase-dependent endothelial invasion + BafA/VEGFR-driven angiogenesis, aided by an IL-10/pro-angiogenic, TH1-suppressed immune milieu) → bleeding dermal angioproliferative nodules (verruga peruana, low mortality, regress with treatment). Endemic to Andean valleys (~1.7M at risk; 28% child seropositivity). Treatment is phase-specific; prevention is vector control.

"During the secondary phase of this disease, bacterial invasion shifts to endothelial cells lining the vasculature." — PMID: 12668141

"Bartonella bacilliformis is a Gram-negative bacterial pathogen that provokes pathological angiogenesis and causes Carrion's disease" — PMID: 35379004

Mechanistic Model / Interpretation

Ordered causal chain (from initiating infection to clinical manifestation)

1.  Phlebotomine sand fly (Lutzomyia verrucarum/Pintomyia spp.) bites human host
        │  leads to
2.  Inoculation of Bartonella bacilliformis into dermis/bloodstream
        │  results in (temperature/pH cues: 20°C, acidic → ialB induction)
3.  Flagella-driven motility + IalA/IalB adhesins engage host cells
        │
        ├──────────────── BRANCH A: ACUTE PHASE (Oroya fever) ────────────────
        │  4A. Adhesins bind erythrocyte spectrin (α/β), band 3, glycophorin A
        │        │  leads to
        │  5A. Trw T4SS pilus–mediated erythrocyte invasion (up to 100% parasitized)
        │        │  results in
        │  6A. Porin A + α/β-hydrolase (Ser205/Asp267/His310) drive hemolysis (80% lysed)
        │        │  leads to
        │  7A. Severe hemolytic anemia + secondary infections (Salmonella)
        │        │  results in
        │  8A. High untreated mortality (Oroya fever)
        │
        └──────────────── BRANCH B: CHRONIC PHASE (verruga peruana) ──────────
           4B. Tropism shifts to dermal vascular endothelial cells (HUVEC-type)
                 │  requires (inferred from in vitro inhibitor studies)
           5B. Host tyrosine-kinase signaling + α5β1 integrin–mediated internalization
                 │  concurrent with
           6B. TH1 suppression (↓IL-6, IP-10, MIG, MIP-1α) + ↑IL-10/pro-angiogenic milieu
                 │  leads to (immune evasion enables persistence)
           7B. BafA autotransporter passenger domain activates VEGF-receptor signaling
                 │  results in
           8B. Endothelial proliferation (up to 3× control) + neovascularization
                 │  produces
           9B. Crops of bleeding angioproliferative dermal nodules (Peruvian wart)
                 │  regress upon
          10B. Clearance of bacterial stimulus (rifampin/azithromycin) — low mortality

Upstream vs downstream. The upstream, shared initiating event is sand fly inoculation and adhesin-mediated cell engagement. The two branches diverge at the level of cellular tropism (erythrocyte vs endothelium), which is the master switch dividing the acute from the chronic phase. Within Branch B, immune modulation (F009) is upstream/permissive, BafA-VEGFR angiogenesis (F002) is the central effector, and the visible nodule (F006) is the downstream manifestation.

Inferred vs demonstrated. Erythrocyte receptors (F013), hemolysis effectors (F004), the BafA-VEGFR axis (F002), and the tropism shift (F013/F014) are experimentally demonstrated. The α5β1-integrin/tyrosine-kinase requirement (F014) is inferred from in vitro inhibitor and antibody-blocking studies (moderate effect sizes), not from in vivo human tissue. The coupling of the IL-10/TH1-suppressed milieu to nodule formation (F009) is an association from cross-sectional human cohorts, not a proven causal step.

Two-tropism comparison

Evidence Base

Consistency and independent corroboration. The two-tropism model rests on multiple independent lines: bacterial genetics (F004, F013, F014), in vitro cell biology (F002, F014), human cohort immunology (F009), and molecular epidemiology (F003, F010). The angiogenesis mechanism is corroborated across a 1990 functional study (1693472) and a 2022 molecular study identifying BafA-VEGFR (35379004) — a 32-year span of consistent findings. No retrieved evidence contradicts the core model.

Limitations and Knowledge Gaps

1. No human genetics. As a purely infectious disease, host-genetic sections of the template (causal genes, variants, inheritance, penetrance, epigenetics, chromosomal abnormalities, carrier/genetic screening, pharmacogenomics) are not applicable. This is a definitive negative finding (F008), not a data gap.
2. Mechanistic steps in Branch B are partly inferred. The α5β1-integrin/tyrosine-kinase requirement (F014) derives from in vitro inhibitor and antibody-blocking assays with moderate effect sizes; it has not been confirmed in human verruga tissue. The causal link between the IL-10/TH1-suppressed milieu (F009) and nodule formation is associative (cross-sectional cohort), not demonstrated by intervention.
3. No robust animal model. Humans are the sole reservoir (F015). There is no naturally occurring animal disease and no genetic model organism; work relies on cellular/in vitro systems and experimental sand fly colonization. This limits in vivo mechanistic and therapeutic testing.
4. Diagnostic sensitivity gaps. Current PCR poorly detects low-bacteremia asymptomatic carriers (F010), meaning prevalence is likely underestimated and the reservoir is imperfectly characterized.
5. Sparse quantitative phenotype data. Frequencies for individual verruga phenotypes (proportion with arthralgia, ulceration, mucosal involvement) and formal quality-of-life measures (EQ-5D/SF-36) are not available in the retrieved literature.
6. Emerging species and resistance underexplored. The clinical spectrum, virulence, and treatment response of B. ancashensis and B. rochalimae, and the prevalence/mechanisms of antibiotic resistance, remain poorly quantified.
7. BafA-VEGFR pathway details. Whether BafA acts directly on VEGFR or via induced host VEGF, and the downstream signaling (PI3K-AKT, MAPK) in verruga endothelium, are not fully resolved.

Proposed Follow-up Experiments / Actions

1. Validate the endothelial-entry receptor in situ. Use immunohistochemistry/spatial transcriptomics on human verruga peruana biopsies to confirm α5β1 integrin engagement and map tyrosine-phosphorylation signaling in lesional endothelium (moving F014 from in vitro inference to in vivo demonstration).
2. Dissect the BafA-VEGFR axis. Test BafA passenger-domain mutants for VEGFR2 binding/phosphorylation, and profile downstream PI3K-AKT/MAPK activation in HUVEC; evaluate anti-VEGF/VEGFR agents (e.g., bevacizumab, kinase inhibitors) as adjuncts to shrink refractory nodules.
3. Develop an improved diagnostic for asymptomatic carriers. Benchmark ultrasensitive/droplet-digital PCR and serologic multiplex assays against latent-class models to close the low-bacteremia detection gap (F010) and better estimate the reservoir.
4. Advance vaccine candidates beyond in silico. Move multi-epitope constructs (Pap31, flagellar biosynthetic protein, heme transporters) into immunogenicity/challenge testing; establish a tractable in vivo or organoid endothelial model for protection assays.
5. Characterize emerging species. Systematic genomic and clinical comparison of B. ancashensis (T4SS+) and B. rochalimae isolates versus B. bacilliformis to define virulence determinants and phase-specific treatment response.
6. Map antibiotic resistance. Surveil rifampin/ciprofloxacin/azithromycin susceptibility across endemic Andean foci; correlate with treatment failure and define resistance mechanisms to guide anti-virulence drug development (e.g., α/β-hydrolase inhibitors building on compound 48/80).
7. Vector-control trial. Evaluate insecticide-treated bed nets plus active case detection/treat-to-clear-reservoir in a cluster-randomized design in high-transmission valleys.

Applicability Notes for the Knowledge Base

• Not applicable (host genetics): causal genes, pathogenic variants, allele frequencies, modifier genes, epigenetics, chromosomal abnormalities, inheritance pattern, penetrance/expressivity, anticipation, mosaicism, founder effects, consanguinity, carrier frequency, genetic testing/screening, pharmacogenomics. Etiology is infectious (F008).
• Pathogen taxonomy (NCBI Taxon): Bartonella bacilliformis, Bartonella ancashensis, Bartonella rochalimae; vectors Lutzomyia verrucarum, Pintomyia robusta; host Homo sapiens (Taxon 9606).
• Key UBERON: skin (0002097), blood (0000178), blood vessel (0001981), liver (0002107), spleen (0002106).
• Key CL: endothelial cell (0000115), erythrocyte (0000232).
• Key GO: angiogenesis (0001525), VEGF receptor signaling (0048010), integrin-mediated signaling (0007229), positive regulation of endothelial cell proliferation (0001938).
• Key NCIT (treatment): Rifampin, Azithromycin, Ciprofloxacin, Chloramphenicol.