The influence of negative regulators of inflammation on C. trachomatis infections

Children'S Hospital & Res Ctr At Oakland, Oakland CA

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Abstract

DESCRIPTION (provided by applicant): Chlamydia trachomatis (CT) is the leading bacterial cause of sexually-transmitted diseases (STD) in humans worldwide. Inflammation is required for elimination of chlamydial infection. Yet, inflammation is also responsible for pelvic inflammatory disease and scarring of fallopian tubes that can lead to infertility, ectopic pregnancy and chronic pelvic pain. While the focus of Chlamydia research has largely been on adaptive immune responses, relatively little is known about negative regulators of inflammation, which can dampen inflammatory responses. Although Toll-like receptors (TLRs) play a role in the initiation of inflammation, the immune response must be downregulated following resolution of infection to avoid the consequences of persistent inflammation. Our Preliminary Studies suggest that phosphatidylinositol 3-kinase (PI3K), which modulates TLR-dependent signaling, inhibits pro-inflammatory gene transcription during CT infection in cervical epithelial cells. Other intracellular mediators block TLR-dependent inflammation at different steps of cell signaling. Our findings for deficiency in one of them, SIGIRR, showed a large effect on outcome of infection in mice, in agreement with our findings that single nucleotide polymorphisms (SNPs) in SIGIRR affect CT infection and tubal pathology in women. Our preliminary results, then, suggest an effect on infection outcome of negative regulators of TLR-mediated signaling - from human cells to mice to humans. Our overall hypothesis is that deficiency in or loss-of-function SNPs in genes involved in negative regulation of TLR-mediated signaling will affect the progression of infection and development of disease, but have the opposite effect from gain-of-function SNPs. Thus, the Aims are to: 1) characterize cytosolic negative regulators of TLR-mediated signaling that could fine tune production of inflammatory cytokines in chlamydiae-infected human cervical epithelial cells, focusing initially on genes involved in negative regulation of inflammation which we have shown to be expressed in these cells: TRIAD3A, SIGIRR, and TRAILR;2) investigate effects of negative regulators (TRIAD3A, SIGIRR, and TRAILR ) of TLRs on the course of infection, challenge and disease pathogenesis in knock out (KO) mice lacking these genes;and 3) assess SNP frequencies in TRIAD3A, SIGIRR, and TRAILR in two geographically and ethnically disparate populations to identify candidate genes associated with susceptibility to CT infection (CT positive vs. CT negative women), symptoms and phenotype/disease (women with and without tubal or cervical pathology). We expect that deletions (KO mice) or (partial or whole) loss-of-function SNPs in any of these genes will result in exacerbation of inflammation during infection in mice and humans. The function, if unknown, of significant SNPs identified in Aim 3 will be investigated by characterizing mutated genes in human epithelial cells in vitro in Aim 1. Our integrated Aims will further our understanding of CT induced inflammation and pathology to develop new approaches, including a vaccine, to control and modulate these globally devastating infections. PUBLIC HEALTH RELEVANCE: Chlamydia trachomatis is the leading worldwide bacterial cause of sexually-transmitted diseases (STD) in humans. Inflammation is required for elimination of Chlamydia infection, but inflammation is also responsible for pelvic inflammatory disease and scarring of upper genital tract fallopian tubes, which can lead to infertility, ectopic pregnancy and chronic pelvic pain. We will investigate the effect of genes involved in turning off inflammation, with the long-term goals of developing interventions to treat infections;developing a vaccine to prevent infection and minimize adverse side effects of the immune response;and identifying individuals at risk for chlamydial STDs and their sequelae, so as to implement early interventions to prevent and eliminate infection.