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Background: Salmonella enterica subsp. enterica serovar Typhi (antigenic formula: 9,12[Vi]:d:–) is a serovar of the O:9 (D1) serogroup. S. Typhi causes typhoid fever, a life-threatening disease that is characterized by sustained fever as high as 103° to 104° F (39° to 40° C). In developed countries, this serovar is considered rare; however, Serovar Typhi is one of the typhoidal Salmonella serovars that cause systemic infections (typhoid or enteric fever). In 1880, Karl Joseph Eberth became the first to observe Salmonella in specimens from typhoid fever patients. The term "typhoid" derives from the Greek "typhōdes" (meaning smoke-like or delirious), reflecting the disease's characteristic symptoms. In 1884, Georg Gaffky successfully isolated this bacillus, which subsequently became known as Salmonella Typhi. According to World Health Organization (WHO), as of 2019, approximately 9 million people contract typhoid annually, resulting in around 110,000 deaths. Common symptoms include persistent fever as high as 39-40°C (103-104°F), fatigue, headache, nausea, abdominal pain, and either constipation or diarrhea. Some individuals may develop a rash, while severe cases can lead to life-threatening complications or death. Although antibiotics such as fluoroquinolones, third-generation cephalosporins, macrolides, and carbapenems are effective for treatment, rising antimicrobial resistance has made managing the disease more challenging. To prevent infection, the typhoid conjugate vaccine (TCV) is recommended for children as young as six months and adults up to 45 or 65 years, depending on the vaccine. Since December 2017, the WHO has prequalified two TCVs, which are now being integrated into childhood immunization programs in typhoid-endemic regions. More specifically, two TCVs are: an inactivated (killed) vaccine given as an injection and a live, attenuated (weakened) vaccine taken orally. The inactivated vaccine is approved for individuals aged 2 years and older, while the oral vaccine is suitable for those 6 years and older. A healthcare provider can help determine the best option based on individual needs. Although routine typhoid vaccination is not advised in US, it is recommended for travelers visiting regions where typhoid fever is common. CDC stated that each year, an estimated 5,700 typhoid cases and 620 related hospitalizations occur in US, with the majority of infections acquired during international travel.

NCBI PD link for serovar Typhi: https://www.ncbi.nlm.nih.gov/pathogens/isolates/#(taxgroup_name:%22Salmonella%20enterica%22)%20AND%20computed_types:(%22serotype=Typhi%22)

Genetic characteristics: Serovar Typhi has been found to be monophyletic. Parkhill et al. sequenced the complete genome (4,809,037 bp) of Salmonella Typhi (CT18) and found this isolate exhibited substantial genetic decay with over 200 pseudogenes, including homologs of key Salmonella Typhimurium virulence genes (e.g., sopE2 and fliB), potentially explaining its human-restricted host specificity. This isolate carries two plasmids: a 218,150 bp multidrug-resistant IncHI1 plasmid (pHCM1) and a 106,516 bp cryptic plasmid (pHCM2) phylogenetically linked to a virulence plasmid of Yersinia pestis. Additionally, it harbors up to 15 Salmonella pathogenicity islands (SPIs 1–7, 9, 11–13, and 15–18). Comparative genomics and phylogenetic analyses have shown that serovar Typhi (i) had a monophyletic origin (ii) emerged approx. 30,000 to 50,000 years ago (iii) belonged to clade A, according to den Bakker et al. (2011) classification, and (iv) had 349 gene families unique to this serovar.

REPJP01, an emerging multidrug-resistant strain of Salmonella Typhi, was first identified in Pakistan (2016) and subsequently reported in US cases (2018). Notably, 90% of clinical isolates demonstrate resistance to five first-line antimicrobials: ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole. Marchello et al. collectively analyzed 55,459 isolates (from 198 studies) and revealed that in Asia (2015–2018), 32.6% of isolates were multidrug-resistant (MDR; resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole in their study), with 5.7% resistant to third-generation cephalosporins and 8.3% to azithromycin. Interestingly, Pakistan reported extensively drug-resistant (XDR) strains (2.6% of isolates; MDR plus fluoroquinolone and cephalosporin resistance). In Africa, MDR prevalence rose steadily each decade (1990–2018), though XDR emergence remains unreported. The H58 haplotype which is MDR has emerged as the dominant Salmonella Typhi lineage, driving widespread epidemics across Asia and Africa. This lineage demonstrates a competitive advantage over other serovar Typhi lineages, particularly with exposure to antimicrobials. While fluoroquinolones remain a frontline treatment, their efficacy is increasingly threatened by resistance mechanisms—notably mutations in gyrA (encoding DNA gyrase subunit A), a key drug target.

Recent studies reveal that the Rab GTPase Rab32 and its guanine nucleotide exchange factor BLOC-3 form a conserved pathway that both restricts Salmonella Typhi to human hosts and mediates its killing in macrophages of non-susceptible species. These proteins, previously recognized for their role in intracellular membrane trafficking—particularly in melanin synthesis through enzyme transport to melanosomes—are now identified as central players in innate immunity against typhoidal Salmonella. Following intestinal invasion, serovar Typhi effectively evades host defenses through multiple mechanisms: it avoids TLR4 recognition, escapes the classical complement pathway, and resists oxidative killing—primarily through production of its protective Vi capsular polysaccharide. More specifically, the TviA regulatory protein orchestrates key virulence strategies through its dual regulatory function: (1) suppressing flagellin-induced inflammatory responses and (2) activating expression of the immunoevasive Vi capsular polysaccharide. These virulence factors are encoded within SPI-7, which harbors the viaB locus (Vi capsule genes) along with additional pathogenicity determinants including type III secretion system, SopE and a type IVB pilus assembly system.

Animal reservoir: Salmonella in developing countries, it is among the top ten Salmonella serovars that caused disease in humans. S. Typhi kills approx. 600.000 people annually. A number of projects have sequenced the genome of strains of S. Typhi; these studies have concluded that S. Typhi is a highly clonal serovar that emerged approx. 30,000-50,000 years ago. In addition, studies have found that horizontal gene transfer plays an important role in the evolution S. Typhi, this included the acquisition of plasmids encoding multiple antibiotic resistant genes in multidrug resistant strains.Animal reservoir: S. Typhi is a human-restricted serovar.

Geographical distribution: S. Typhi Serovar Typhi is widely globally distributed; however, the prevalence of this serovar varies considerable. In developed countries (U.S., Canada, Europe), S. Typhi isolations correspond to less than 1% of all Salmonella serovars isolated from humans. In developing countries, S. Typhi isolations correspond to up to. 30% of all Salmonella isolated in some countries in Latin America and Asia.Outbreaks: Salmonella Typhi has caused multiple outbreaks in the U.S. and Europe. In developing countries with endemic presence of typhoidal Salmonella, outbreaks are mostly undetected. On large outbreak (5,963 cases), was reported in Nepal. Crump et al. concluded that typhoid fever incidence is highest in south-central and southeast Asia, with over 100 cases per 100,000 people annually. Medium incidence rates (10–100 cases per 100,000 per year) are found in other parts of Asia, Africa, Latin America, the Caribbean, and Oceania (excluding Australia and New Zealand). In contrast, Europe, North America, and other developed regions report low typhoid fever rates, with fewer than 10 cases per 100,000 people each year.

Human outbreaks: Multiple human outbreaks linked to serovar Typhi has been reported. Below are some examples. 

Relevant links and references:

¹ The outbreak was associated with travel to Kos, Greece. 

Border rejections: There have been no recent border rejections linked to this serovar. 

Recalls: 

¹ This recall was caused by a multistate outbreak described above. Goya Foods, Inc. and Montalvan’s Sales, Inc. issued voluntary recalls of their fruit pulp products.  

Relevant links:

1. https://pubmed.ncbi.nlm.nih.gov/25208300/
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7706954/
3. https://www.who.int/news-room/fact-sheets/detail/typhoid#:~:text=As%20of%202019%20estimates%2C%20there,children%20are%20at%20highest%20risk
4. https://www.cdc.gov/vaccines/hcp/current-vis/typhoid.html
5. httpshttp://www.cdc.gov/salmonellatyphoid-fever/typhoidfeverabout/index.html
6. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2025.1547190/full
7. httpshttp://www.scielo.br/scielo.php?pid=S1517-83822009000100029&script=sci_arttext
8. http://jcm.asm.org/content/42/4/1477.full
9. http://cid.oxfordjournals.org/content/45/Supplement_1/S29.full
10. nature.com/articles/35101607
11. https://academic.oup.com/cid/article/45/Supplement_1/S29/357357?login=true
12. https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-12-425
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC3175032/
14. https://www.cdc.gov/typhoid-fever/php/rep-strain/index.html
15. https://pmc.ncbi.nlm.nih.gov/articles/PMC7695120/
16. https://www.annualreviews.org/deliver/fulltext/micro/68/1/annurev-micro-091313-103739.pdf?itemId=/content/journals/10.1146/annurev-micro-091313-103739&mimeType=application/pdf
17. https://link.springer.com/chapter/10.1007/978-3-319-32189-9_17
18. https://academic.oup.com/femsre/article/45/5/fuab014/6159486
19. https://www.nature.com/articles/s41572-023-00480-z
20. https://academic.oup.com/femsre/article/45/5/fuab014/6159486
21. https://pmc.ncbi.nlm.nih.gov/articles/PMC6128363/
22. https://pmc.ncbi.nlm.nih.gov/articles/PMC2622843/
23. https://www.theguardian.com/world/2023/apr/02/typhoid-outbreak-on-refugee-ship-in-netherlands-traced-to-raw-sewage
24. https://archive.cdc.gov/www_cdc_gov/salmonella/2010/frozen-fruit-pulp-8-25-10.html#:~:text=Outbreak%20Investigation&text=Among%20interviewed%20ill%20persons%2C%207,brand%20frozen%20mamey%20fruit%20pulp.
25. https://pubmed.ncbi.nlm.nih.gov/15712078/
26. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/216736
27. https://www.jstor.org/stable/30085190?seq=1
28. https://pubmed.ncbi.nlm.nih.gov/11092435/
29. https://pmc.ncbi.nlm.nih.gov/articles/PMC2490935/
30. https://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.28.5.644
31. https://ajph.aphapublications.org/doi/10.2105/AJPH.2023.307434
32. https://pmchttp://www.ncbi.nlm.nih.gov/articles/pubmedPMC3959940/11677608