AUTHOR=Zhong Wujuan , Kollipara Avinash , Liu Yutong , Wang Yuhan , O’Connell Catherine M. , Poston Taylor B. , Yount Kacy , Wiesenfeld Harold C. , Hillier Sharon L. , Li Yun , Darville Toni , Zheng Xiaojing 

TITLE=Genetic susceptibility loci for Chlamydia trachomatis endometrial infection influence expression of genes involved in T cell function, tryptophan metabolism and epithelial integrity

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1001255

DOI=10.3389/fimmu.2022.1001255

ISSN=1664-3224

ABSTRACT=<sec><title>Objectives</title><p>Identify genetic loci of enhanced susceptibility to <italic>Chlamydial trachomatis (Ct)</italic> upper genital tract infection in women.</p></sec><sec><title>Methods</title><p>We performed an integrated analysis of DNA genotypes and blood-derived mRNA profiles from 200 <italic>Ct-</italic>exposed women to identify expression quantitative trait loci (eQTL) and determine their association with endometrial chlamydial infection using a mediation test. We further evaluated the effect of a lead eQTL on the expression of <italic>CD151</italic> by immune cells from women with genotypes associated with low and high whole blood expression of <italic>CD151</italic>, respectively.</p></sec><sec><title>Results</title><p>We identified <italic>cis</italic>-eQTLs modulating mRNA expression of 81 genes (eGenes) associated with altered risk of ascending infection. In women with endometrial infection, eGenes involved in proinflammatory signaling were upregulated. Downregulated eGenes included genes involved in T cell functions pivotal for chlamydial control. eGenes encoding molecules linked to metabolism of tryptophan, an essential chlamydial nutrient, and formation of epithelial tight junctions were also downregulated in women with endometrial infection. A lead eSNP rs10902226 was identified regulating <italic>CD151</italic>, a tetrospanin molecule important for immune cell adhesion and migration and T cell proliferation. Further <italic>in vitro</italic> experiments showed that women with a CC genotype at rs10902226 had reduced rates of endometrial infection with increased <italic>CD151</italic> expression in whole blood and T cells when compared to women with a GG genotype.</p></sec><sec><title>Conclusions</title><p>We discovered genetic variants associated with altered risk for <italic>Ct</italic> ascension. A lead eSNP for <italic>CD151</italic> is a candidate genetic marker for enhanced CD4 T cell function and reduced susceptibility.</p></sec>