The role of Perforin-2 in Chlamydia pathogenesis

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 DESCRIPTION (provided by applicant): Sexually transmitted disease mediated by bacterial pathogens represents a significant burden to human health world-wide. Chlamydia trachomatis remains the most prevalent of reportable cases in the U.S. and infections can lead to sequelae such as ectopic pregnancy, sterility, and pelvic inflammatory disease. While adaptive immunity is essential for clearance of Chlamydia in a murine model, chlamydial infections elicit a robust innate immune response that has been correlated with limiting ascension of infection as well as host tissue pathology. We have recently identified a novel innate immune factor termed Perforin-2 that is capable of killing a wide range of cell-associated bacteria. These observations make it likely that P-2 is a pivotal host factor involved in combating bacterial infection. An obligate intracellular existence like the one exemplified by Chlamydia spp. necessitates evolution of mechanisms to evade or circumvent innate host defenses that would normally neutralize invading microbes. Our preliminary data indicate that Chlamydia block P-2 activity in permissive cells but are susceptible to P-2 mediated killing in non-permissive cells like macrophages. We will take advantage of both in vitro tissue culture and in vivo murine infection models to elucidate the molecular mechanisms governing the sensitivity or resistance of Chlamydiae to P-2-mediated killing. Overall, we seek to understand host and bacterial factors that significantly influence the outcome of infection. This study will contribute to that overall gal by studying the infection biology of an important human pathogen and a newly appreciated and essential component of host immunity.