Infection Prevention and Control

Biography

Biography: Stephanie Fresnay1, Monica A McArthur1, Thomas C Darton2, Claire Jones2, Claire S Waddington2, Christoph J Blohmke2, Brian Angus2, Myron M Levine1, Andrew J Pollard2 and Marcelo B Sztein1

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-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a) in distinct T cell memory subsets. Pre-challenge production of IFN-g, TNF-α and MIP-1β by S. Typhi-specific CD8⁺ multifunctional T effector memory (T_EM) 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 a₄b₇-and integrin a₄b₇+CD8+ T_EM 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+ T_EM 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 wild-type 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.