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Abstract

Salmonella enterica serovar Typhi (S. Typhi) is a human restricted pathogen which causes significant morbidity and mortality, particularly in developing countries. A better understanding of the immune responses which result in protection from S. Typhi infection is imperative for the development of improved attenuated vaccines. Recently, a controlled human infection model was re-established in which participants received ~104 cfu wild-type S. Typhi (Quailes strain) orally. 20 participants were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 28 days after challenge were exposed to 3 S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously 5 intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-�³, TNF-�± and MIP-1�²) and a marker of degranulation/cytotoxic activity (CD107a) in distinct T cell memory subsets. Pre-challenge production of IFN-�³, TNF-�± and MIP-1�² by S. Typhi-specific CD8+ multifunctional T effector memory (TEM) following exposure to S. Typhi-infected targets were higher in most participants who develop infection. Early decreases were observed in both S. Typhi-specific integrin �±4�²7-and integrin �±4�²7+CD8+ TEM cells after challenge, suggesting a potential for these cells to home to mucosal, as well as to extra-intestinal sites. Higher baseline S. Typhi-specific CD8+ TEM responses also correlated with delayed typhoid diagnosis. No changes in these responses were found in NoTD participants after challenge. These studies demonstrate that S. Typhi-specific CD8+ baseline responses correlate with clinical outcome in humans challenged with wildtype S. Typhi, and provide novel insights into the protective immune responses against typhoid disease that will aid in the selection and development of new vaccine candidates.

Biography

Stephanie Fresnay is a Postdoctoral Fellow in the Cellular Immunology Section of the Center for Vaccine Development at the University of Maryland, USA. She is a Co-Investigator for the clinical trial entitled “Understanding Typhoid Disease: Development of a Salmonella Typhi Challenge Model in Healthy Adults” and has published in the Journal of Translational Medicine. She is also the co-author of several papers investigating regulatory T cells and antigen presenting cells function after challenge with wild-type S. Typhi as well as the co-author of a study characterizing S. Typhi, S. Paratyphi A and S. Paratyphi B cross-reactive CD4+ T cell responses elicited following vaccination.

Email: sfresnay@hotmail.com sfresnay@medicine.umaryland.edu