Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), results in a life-threatening systemic disease that is responsible for significant morbidity and mortality annually worldwide. The disease is endemic in many parts of Africa, including Kenya. 1-5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the site of persistence. S. Typhi is a human-restricted pathogen, therefore asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model and in humans, serving as a substrate to which salmonellae attach and form a protective biofilm. However, the epidemiology regarding the development of Salmonella chronic carriage and spread of the disease from both acute and chronic carriers is poorly understood. In this proposal, we intend to prospectively study a population in a typhoid fever endemic region in Kenya to better understand: (1) genomics, antibiotic resistance and biofilm phenotypes of the S. Typhi strains causing typhoid fever and chronic carriage, (2) the linkage of GSs to the establishment of chronic carriers, and (3) the local epidemiology and geospatial distribution of typhoid fever in the target urban community. Modeling the data gathered will allow a greater understanding of the strains causing acute and chronic infection and the associated epidemiologic factors contributing to S. Typhi spread in a community. This will also help healthcare practitioners better treat and predict the likelihood of disease transmission as well as asymptomatic carriage.

Public Health Relevance

Salmonella Typhi causes typhoid fever in humans. 1-5% of those with typhoid fever become asymptomatic chronic carriers primarily due to biofilm formation on gallstones. In this proposal, we will study the epidemiology of disease, genetic and phenotypic traits of the strains, and the association of the infection with gallstones of patients in Kenya where typhoid fever is prevalent. The findings will help better understand the transmission of typhoid fever and the development of chronic carriers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI099525-06A1
Application #
9930169
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Alexander, William A
Project Start
2013-02-15
Project End
2025-03-31
Budget Start
2020-04-02
Budget End
2021-03-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Kenya Medical Research Institute (KEMRI)
Department
Type
DUNS #
644035891
City
Nairobi
State
Country
Kenya
Zip Code
00200
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Feasey, Nicholas A; Hadfield, James; Keddy, Karen H et al. (2016) Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings. Nat Genet 48:1211-1217
Kariuki, Samuel; Okoro, Chinyere; Kiiru, John et al. (2015) Ceftriaxone-resistant Salmonella enterica serotype typhimurium sequence type 313 from Kenyan patients is associated with the blaCTX-M-15 gene on a novel IncHI2 plasmid. Antimicrob Agents Chemother 59:3133-9
Kariuki, Samuel; Onsare, Robert S (2015) Epidemiology and Genomics of Invasive Nontyphoidal Salmonella Infections in Kenya. Clin Infect Dis 61 Suppl 4:S317-24
Wong, Vanessa K; Baker, Stephen; Pickard, Derek J et al. (2015) Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat Genet 47:632-9
Kariuki, Samuel; Gordon, Melita A; Feasey, Nicholas et al. (2015) Antimicrobial resistance and management of invasive Salmonella disease. Vaccine 33 Suppl 3:C21-9
Kariuki, Samuel; Dougan, Gordon (2014) Antibacterial resistance in sub-Saharan Africa: an underestimated emergency. Ann N Y Acad Sci 1323:43-55