Abstract
ABSTRACTInsights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum. Immunization with one of two live oral attenuated vaccines against S. Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S. Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S. Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S. Typhi.
Highlights
IntroductionOur observations have important implications in interpreting the efficacy of oral attenuated vaccines against enteric pathogens in diverse populations
Typhi Quailes strain and the effects on the composition and function of the gut microbiota, we carried out longitudinal 16S rRNA gene and metatranscriptomic analyses of stool samples obtained from 30 healthy adult trial subjects who were randomly assigned to one of the three vaccine groups in a study performed in Oxford, United Kingdom [13]
We evaluated the quality of the RNA sequencing (RNA-seq) results by quantitative reverse transcriptase PCR, using a subset of genes that were differentially expressed between the two transcriptome communities
Summary
Our observations have important implications in interpreting the efficacy of oral attenuated vaccines against enteric pathogens in diverse populations. Reduced vaccine efficacy and immunogenicity in resource-limited regions have been reported with other vaccines, including rotavirus and oral polio vaccines [8, 11, 12] Despite these limitations, live attenuated oral vaccines continue to have great potential to reduce disease transmission and prevent clinical infection around the world. Live attenuated oral vaccines continue to have great potential to reduce disease transmission and prevent clinical infection around the world Through studies such as those presented here, there is the potential for new insights that may be leveraged to improve protective efficacy of oral vaccines against typhoid and other enteric infections
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