Salmonella typhi
Gram-negative, non-spore-forming, facultatively anaerobic rod; strictly human host. Vi polysaccharide capsule shields LPS O-antigen from TLR4 and complement opsonisation, enabling systemic bacteraemia. SPI-1 T3SS (SopE, SopB, SipA, SipC effectors) triggers macropinocytosis-like uptake by ileal M cells; SPI-2 T3SS maintains the Salmonella-containing vacuole (SCV) against lysosomal fusion within macrophages — enabling systemic dissemination to liver, spleen, and bone marrow. Typhoid toxin (CdtB DNase + PltA ADP-ribosyltransferase + PltB A⊂2;B⊂5; pentamer) is secreted from the SCV and causes DNA damage, neurological manifestations, and facilitates chronic carriage. ~1–4% of convalescents become chronic gallbladder carriers. XDR typhoid (Pakistan clade 4.3.1, 2016) resists chloramphenicol, ampicillin, TMP-SMX, fluoroquinolones, and third-generation cephalosporins.
Classification & Structure
| Gram reaction | Gram-negative; LPS O-antigen serogroup D (O9,12); Kauffmann-White scheme serogrouping |
| Morphology | Non-spore-forming rod, 2–3 µm × 0.5–0.8 µm; peritrichous flagella (H antigen: d, monophasic); motile; lactose non-fermenter, H⊂2;S negative (unlike S. Typhimurium), indole negative |
| Cell wall / Capsule | Vi polysaccharide (2-N-acetyl-4-amino-deoxy-galacturonic acid polymer; ~90% of clinical isolates): shields LPS O-antigen from TLR4/MD-2 and C3b deposition; inhibits TLR5 (flagellin shielding); serum resistance during bacteraemia; primary vaccine antigen target |
| Key virulence factors | Vi capsule; SPI-1 T3SS (M-cell invasion: SopE/E2, SopB, SipA, SipC); SPI-2 T3SS (SCV maintenance: SifA, SseJ, SseF/G, SspH2/SseI); Typhoid toxin (CdtB + PltA + PltB A⊂2;B⊂5;); biofilm on gallstones (chronic carrier state) |
| Genome | 4.8 Mb; ~4,600 coding sequences; ~200 pseudogenes (host-restriction gene decay vs. broad-host Salmonella); IncHI1 plasmid in XDR clade 4.3.1 mediates multi-class resistance including blaCTX-M-15 |
Pathogenesis
1 · Fecal-oral transmission and gastric transit
Transmitted via contaminated water or food (sewage-irrigated produce, shellfish). Infectious dose ~10³–10&sup5; CFU; Vi capsule protects from gastric acid via an inducible acid tolerance response. Chronic gallbladder carriers shed 10&sup6;–10&sup9; CFU/g stool intermittently and are the primary perpetual transmission reservoir in endemic communities.
2 · SPI-1 T3SS M-cell invasion (Days 1–7)
Bacteria preferentially target M cells overlying Peyer’s patches of the terminal ileum — specialised antigen-sampling cells with efficient transcytotic capacity. The SPI-1 T3SS needle injects: SopE/E2 (GEFs → Rac1/Cdc42 → actin polymerisation); SopB (PI phosphatase → membrane ruffling); SipA (actin stabilisation); SipC (actin nucleation). Result: macropinocytosis-like bacterial uptake. Bacteria are transcytosed, deposited subepithelially, and phagocytosed by resident macrophages.
3 · SPI-2 T3SS intracellular survival (Days 3–14)
Within macrophages, S. Typhi resides in the Salmonella-containing vacuole (SCV). As SCV acidifies to pH ~5.0, SPI-2 is induced: SifA recruits LAMP1+ late endosomal membranes; SseJ esterifies cholesterol in SCV membrane; SseF/SseG tether SCV to Golgi for nutrient supply; SspH2/SseI dampen NF-κB and DC chemotaxis. Net result: SCV resists lysosomal fusion, avoids ROS, becomes a protected replication niche.
4 · Systemic dissemination and gallbladder carriage (Days 7–21)
Infected macrophages travel via lymphatics to the thoracic duct and into the bloodstream producing sustained low-grade bacteraemia (<10 CFU/mL). Bacteria seed Kupffer cells (hepatomegaly), splenic macrophages (splenomegaly), and bone marrow macrophages maintaining bacteraemia. The gallbladder is colonised via bile, forming biofilm on gallstones — the chronic carrier reservoir (~1–4% of convalescents; “Typhoid Mary” prototype). Typhoid toxin (CdtB DNase + PltA ADP-ribosyltransferase) exported from SCV causes typhoid encephalopathy and potentially stabilises the carrier state.
5 · XDR typhoid emergence (H58/clade 4.3.1, Pakistan 2016)
The XDR lineage carries an IncHI1 plasmid encoding resistance to: chloramphenicol (catA1), ampicillin (blaTEM-1), TMP-SMX (dfrA7, sul1/2), fluoroquinolones (qnrS + chromosomal gyrA D87N), and extended-spectrum cephalosporins (blaCTX-M-15). Treatment of complicated XDR typhoid is now limited to IV carbapenems (meropenem, ertapenem). Azithromycin-resistant XDR strains are emerging, representing a pre-total drug resistance state.
Host Immune Response
Disease Spectrum (Typhoid Fever)
| Week | Clinical features | Pathological correlate |
|---|---|---|
| Week 1 | Stepwise rising fever to 39–40°C by day 5–7; headache, malaise; relative bradycardia (Faget’s sign) | Primary bacteraemia from intestinal translocation; macrophage seeding of liver/spleen |
| Week 2 | Sustained fever; splenomegaly, hepatomegaly; rose spots (10–30%); “pea soup” diarrhoea or constipation | Peak bacteraemia; Kupffer cell/splenic macrophage infection; Peyer’s patch hyperplasia |
| Week 3 | Intestinal perforation (0.8–3%), haemorrhage (2–8%), typhoid encephalopathy, myocarditis, nephritis | Peyer’s patch ulceration/necrosis from re-invasion; maximal organ involvement |
| Week 4 | Gradual defervescence in survivors; relapse risk ~5–10% with suboptimal treatment | Immune clearance; residual macrophage foci; gallbladder colonisation beginning |
Treatment & Prophylaxis
| Fluoroquinolones (susceptible) | Ciprofloxacin 500 mg BID ×7–10 days; rapid defervescence (3–5 days); high intracellular penetration. First-line for fully susceptible strains only. |
| Azithromycin | 1 g loading then 500 mg/day ×7 days PO; safe in children and pregnancy; first-line for uncomplicated XDR typhoid and fluoroquinolone-resistant strains. Azithromycin-resistant XDR strains emerging. |
| XDR typhoid treatment | Meropenem or ertapenem IV for severe/complicated XDR typhoid; reserve agents. Active microbiological surveillance for azithromycin and carbapenem resistance essential. |
| Ty21a oral vaccine | Live-attenuated; 3–4 doses; ~50–70% efficacy; cold chain required; contraindicated <5 years and immunocompromised. Travel and outbreak use. |
| Vi-PS vaccine (Typhim Vi) | Unconjugated Vi polysaccharide; single IM dose; ~55–72% efficacy; not immunogenic <2 years; no T-cell memory; waning immunity. Travel and programmatic use ≥2 years. |
| Typbar-TCV (Vi-CRM197) | Vi polysaccharide conjugated to CRM197 carrier protein; WHO-prequalified 2017; ~81.6% efficacy in Nepal RCT; immunogenic from 6 months; T-cell memory; single injection; deployed in Gavi-supported campaigns in South Asia and sub-Saharan Africa. Preferred for programmatic use and endemic settings. |
Cross-Atlas Connections
References
- Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med. 2002;347(22):1770–82. doi:10.1056/NEJMra020201 · PubMed 12456854
- Crump JA. Progress in typhoid fever epidemiology. Clin Infect Dis. 2019;68(Suppl 1):S4–S9. doi:10.1093/cid/ciy846 · PubMed 30767000
- World Health Organization. Typhoid vaccines: WHO position paper, March 2018. Wkly Epidemiol Rec. 2018;93(13):153–172. who.int/publications/i/item/who-wer9313
- Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020.
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This entry covers typhoid fever pathogenesis, XDR typhoid, and vaccine deployment. Planned expansions: typhoid toxin mechanism, scRNA-seq of macrophage/SCV interaction, and WASH intervention modelling for global burden reduction.