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
1University of Maryland, USA
2University of Oxford, UK
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.
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 (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 a4b7-and integrin a4b7+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 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.
Speaker PPTsDownload PPT