Abstract
BackgroundTyphoid 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.MethodsRecently, a controlled human infection model was re-established in which volunteers received ~103 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).ResultsHerein 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 (TEM) 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 TEM.ConclusionsThese 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 materialThe online version of this article (doi:10.1186/s12967-016-0819-7) contains supplementary material, which is available to authorized users.
Highlights
Typhoid fever, caused by the human-restricted organism Salmonella Typhi
Typhi‐specific CD8+ T cell responses correlate with clinical outcome after challenge CD8+ T cells have been reported to be a major component of the cell-mediated immune (CMI) response against S
Peripheral blood mononuclear cells (PBMC) were evaluated using 14-color multiparametric flow cytometry and CD8+ T cells were divided based on their expression of CD62L and CD45RA into naïve T (TN; CD62L+CD45RA+), T central memory (TCM; CD62L+CD45RA−), T effector memory (TEM; CD62L− CD45RA−), and T effector memory CD45RA+ (TEMRA; CD62L−CD45RA+) subsets
Summary
Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Methods: Recently, a controlled human infection model was re-established in which volunteers received ~103 cfu wild-type S. The development of improved vaccines is necessary, but advances have been delayed by a lack of Recently, a human challenge model was established by the Oxford Vaccine Group (OVG, University of Oxford) in which naïve participants ingested wild-type (wt) S. Typhi (Quailes strain) [3, 4] This controlled infection study was modeled after the human typhoid challenge studies performed in the 1960s at the University of Maryland. The Maryland studies improved understanding of typhoid fever [5,6,7,8] and resulted in the initiation of the process to license the oral attenuated Ty21a typhoid vaccine [9], but did not identify the immunological correlates of protection. Substantial data are available on the immune responses after infection in the field or following vaccination, there are no studies that provide insights into the immunological status before wild-type infection and its possible effects on clinical outcome
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