期刊
JOURNAL OF TRANSLATIONAL MEDICINE
卷 14, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12967-016-0819-7
关键词
Typhoid fever; Salmonella Typhi; Cell-mediated immunity; CMI; CD8 T cells; Multifunctional; Cytotoxicity; Cytokines
资金
- Wellcome Trust [092661]
- NIHR Oxford Biomedical Research Centre [Clinical Research Fellowships]
- Jenner Institute, the Oxford Martin School, the European Union [FP7, Marie Curie Research Fellowship]
- NIAID, NIH, DHHS grants [R01-AI036525, U19 AI082655, U19-AI109776]
- Passano Foundation Clinical Investigator Award
- NIH Fellowship Training Program in Vaccinology [T32-AI07524]
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 similar to 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 TEM. 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.
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