Background Typhoid fever, caused by the human-restricted organism Salmonella Typhi ( S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. Methods Recently, a controlled human infection model was re-established in which volunteers received ~10 3 cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three 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 five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). Results Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (T EM ) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S . Typhi-specific T EM . Conclusions These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0819-7) contains supplementary material, which is available to authorized users.
【저자키워드】 Cytokines, cytotoxicity, CD8 T cells, Cell-mediated immunity, typhoid fever, Salmonella Typhi, CMI, multifunctional,