Friday, May 9, 2025
5/9/2025
Chlamydia trachomatis evades a novel IL32-mediated immune resistance program - ABSTRACT Chlamydia trachomatis (Ct) represents the most common sexually transmitted bacterium in the U.S., and is responsible for severe sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. No vaccine is currently available. Much of what makes Ct such an effective pathogen is its ability to evade the host immune response. The molecular mechanisms of this immune evasion remain largely uncharacterized, and represent a major gap in knowledge which is necessary for the proper prevention of this disease. Chlamydia species invade host epithelial cells, where they establish infection within a membrane-bound vacuole called an “inclusion”. At least two closely-related species of Chlamydia can infect human epithelial cells: C. trachomatis (Ct) and C. muridarum (Cm). Once inside these epithelial cells, Cm is vulnerable to clearance by intracellular defenses galvanized by interferon-γ (IFNγ), while Ct is able to expertly evade these defenses and will grow uninhibited. These IFNγ-induced defenses, and their evasion by Ct, are poorly understood phenomena in need of further research. We recently discovered that a human IFNγ-stimulated gene (ISG) drives restriction of Cm through an intracellular, proteasome-dependent mechanism. I also found that the Ct gene IncS confers protection against this ISG. In the following proposal, I propose experiments to better understand how Ct IncS drives evasion of human IFNγ-stimulated host defense. These experiments will include comparisons between Cm and Ct IncS function, and will focus on the role of two host proteins recruited by Ct IncS: STIM1/2. Our hypothesis is that Ct recruits STIM1/2 as a form of “molecular camouflage” to hide individual inclusions from host recognition and immune clearance. I will also propose experiments to better understand how the proteasome defends against Cm. I will perform several experiments to determine whether the proteasome directly localizes to Cm and if it degrades bacterial proteins to clear Cm infection. I will also perform a proteomics screen to identify additional protein partners involved in IFNγ-mediated restriction of Cm. Together, these experiments will provide a better understanding of intracellular defenses within the human epithelium and will characterize a novel mechanism of immune evasion by C. trachomatis. Through characterizing host-pathogen interactions during Chlamydia infection, we hope to guide the design of improved options to prevent and treat chlamydial disease.
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