Induction of Cell Cycle and NK Cell Responses by Live-Attenuated Oral Vaccines against Typhoid Fever.

Frontiers in Immunology
Christoph J BlohmkeAndrew J Pollard

Abstract

The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Salmonella Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens.

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Citations

Aug 31, 2019·EMBO Molecular Medicine·Christoph J BlohmkeThomas C Darton
Dec 24, 2019·Human Vaccines & Immunotherapeutics·Patrícia Gonzalez-DiasHelder I Nakaya
Jul 30, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Stephen BakerThomas C Darton
Jan 13, 2018·Frontiers in Immunology·Amber J BartonChristoph J Blohmke
Jun 1, 2018·The Cochrane Database of Systematic Reviews·Rachael MilliganAmi Neuberger
Jan 7, 2021·International Immunology·Divy DhingraDipshikha Chakravortty
Mar 19, 2021·FEMS Microbiology Reviews·Amber J BartonAndrew J Pollard

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Datasets Mentioned

BETA
GSE100665

Methods Mentioned

BETA
ELISA
Flow Cytometry

Clinical Trials Mentioned

NCT01405521

Software Mentioned

GSEA
ssGSEA
limma
Cytoscape
InnateDB
GenomeStudio
R
Gene Set Enrichment Analysis ( GSEA )
WGCNA package
Bioconductor

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