Understanding Host Epigenetic changes to Salmonella Typhi Exposure and Infection in the context of a Human Challenge Model

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Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A is an important cause of morbidity and mortality. Around 21 million people per year develop enteric fever of which approximately 222,000 die, with children being most at risk. The majority of cases arise in South-Central and Southeast Asia. There are several key challenges in preventing and managing typhoid infection including: difficulties in diagnosing enteric fever as current tests have poor sensitivity; short term vaccine efficacy, with no licensed vaccine for children under two years old; and the emergence of antibiotic resistant strains. Novel biomarkers of infection, more efficacious vaccines and novel anti-typhoid therapies are therefore needed; achieving these goals requires a better understanding of immune response to typhoid and in particular the role of innate and adaptive cellular immunity.Enteric fever challenge studies, in which adults are challenged with a dose of typhoid bacteria with an attack rate of 65% in non-immune participants are currently being employed in Oxford to study immunity to these Salmonellae. Preliminary data show that infection, and vaccination alters gene expression in leukocytes and that these changes are associated with both immune responses and the inflammatory response during disease. How and why this occurs is governed by epigenetic mechanisms including DNA methylation and miR expression. MicroRNAs are a species of short non-coding RNA that post transcriptionally regulate 60% of genes. They are important mediators of host response to infection. MiRs are implicated in immune response e.g. miR-155 promotes an antimicrobial response by suppressing SOCS1 (suppression of cytokine signalling 1)to promote leukocyte secretion of pro-inflammatory cytokines4. MicroRNAs regulate differentiation and activation of B-cells, T-cells, monocytes and dendritic cells and therefore may govern host susceptibility to typhoid5-7. Typhoid challenge studies present the opportunity to delineate immune response to a bacterial pathogen, at an epigenetic level, in a uniquely controlled environment. This study will use small RNA sequencing techniques and methylation chips to characterise microRNA and gene methylation changes after typhoid exposure and during typhoid infection in the PBMCs of participants of an enteric fever challenge study using stored samples. Epigenetic and pre-derived transcriptomic data will be integrated to provide an unprecedented level of detail in gene expression during exposure and infection. The functional significance of DNA methylation patterns and microRNAs will be determined using in-vitro studies. Data from this project could identify novel microRNA biomarkers of typhoid or bacterial infection, and may provide biological insights into the proteins and pathways which promote or prevent typhoid infection which could be exploited to facilitate the design of novel typhoid vaccines or anti-typhoid therapeutics.