The role of Perforin-2 in Chlamydia pathogenesis

 描述(申请人提供)：由细菌病原体介导的性传播疾病在世界范围内对人类健康构成重大负担。沙眼衣原体仍然是美国最常见的报告病例，感染可导致宫外孕、不孕症和盆腔炎等后遗症。虽然获得性免疫对于清除小鼠模型中的衣原体至关重要，但衣原体感染引发了强大的先天免疫反应，这与限制感染的上升以及宿主组织的病理有关。我们最近发现了一种新的先天性免疫因子，称为穿孔素-2，它能够杀死广泛的细胞相关细菌。这些观察结果表明，P-2可能是参与对抗细菌感染的关键宿主因子。一种专性的细胞内存在，例如衣原体。这就需要进化机制来逃避或绕过通常可以中和入侵微生物的固有宿主防御。我们的初步数据表明，衣原体在允许的细胞中阻断P-2的活性，但在非允许的细胞如巨噬细胞中对P-2介导的杀伤敏感。我们将利用体外组织培养和体内小鼠感染模型来阐明衣原体对P-2介导的杀伤敏感或耐药的分子机制。总体而言，我们试图了解显著影响感染结果的宿主和细菌因素。这项研究将通过研究一种重要的人类病原体和新认识的宿主免疫的重要组成部分的感染生物学来促进GAL的全面发展。

 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.