Abstract
Background Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever. Cellular immune responses are required to control and clear Salmonella infection. Despite this, there are limited data on cellular immune responses in humans infected with wild type S. Typhi.Methodology/Principal FindingsFor this work, we used an automated approach to purify a subset of S. Typhi proteins identified in previous antibody-based immuno-affinity screens and antigens known to be expressed in vivo, including StaF-putative fimbrial protein-STY0202, StbB-fimbrial chaperone-STY0372, CsgF-involved in curli production-STY1177, CsgD- putative regulatory protein-STY1179, OppA-periplasmic oligopeptide binding protein precursor-STY1304, PagC-outer membrane invasion protein-STY1878, and conserved hypothetical protein-STY2195; we also generated and analyzed a crude membrane preparation of S. Typhi (MP). In comparison to samples collected from uninfected Bangladeshi and North American participants, we detected significant interferon-γ responses in PBMCs stimulated with MP, StaF, StbB, CsgF, CsgD, OppA, STY2195, and PagC in patients bacteremic with S. Typhi in Bangladesh. The majority of interferon-γ expressing T cells were CD4 cells, although CD8 responses also occurred. We also assessed cellular proliferation responses in bacteremic patients, and confirmed increased responses in infected individuals to MP, StaF, STY2195, and PagC in convalescent compared to acute phase samples and compared to controls. StaF is a fimbrial protein homologous to E. coli YadK, and contains a Pfam motif thought to be involved in cellular adhesion. PagC is expressed in vivo under the control of the virulence-associated PhoP-regulon required for intra-macrophage survival of Salmonella. STY2195 is a conserved hypothetical protein of unknown function.Conclusion/SignificanceThis is the first analysis of cellular immune responses to purified S. Typhi antigens in patients with typhoid fever. These results indicate that patients generate significant CD4 and CD8 interferon-γ responses to specific S. Typhi antigens during typhoid fever, and that these responses are elevated at the time of clinical presentation. These observations suggest that an interferon-γ based detection system could be used to diagnose individuals with typhoid fever during the acute stage of illness.
Highlights
Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever
We report the assessment of cellular immune responses in humans with S
Antigen-specific interferon-c responses were present at the time of clinical presentation in patients and absent in healthy controls. These observations could assist in the development of interferon-c-based diagnostic assays for typhoid fever
Summary
Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever. Typhi infection occur each year, resulting in approximately 200,000 deaths per year globally [1]. Current typhoid vaccines provide 50–75% protection for 2–5 years [2]. Mediators of protective immunity against typhoid are incompletely understood. With the exception of antibody responses against the S. Typhi capsule (Vi antigen) [12], antibody responses may play a limited role in mediating protective immunity during typhoid fever. Cellular immune responses are required to control and clear Salmonella infection. There are limited data on cellular immune responses in humans infected with wild type S.
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