The role of Perforin-2 in Chlamydia pathogenesis

Perforin-2 在衣原体发病机制中的作用

• 批准号: 9128331
• 负责人: KENNETH A FIELDS
• 金额: $ 38.33万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128331
• 关键词: Address; Affect; Amoeba genus; Anti-Bacterial Agents; Area; Bacteria; Bacterial Infections; Biochemical; Biology; Cells; Cellular biology; Characteristics; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chlamydiales; Data; Development; Disease; Economic Burden; Ectopic Pregnancy; Epithelial Cells; Equilibrium; Eukaryota; Event; Evolution; Growth; Health; Host Defense; Human; Image; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Integration Host Factors; Invaded; Knockout Mice; Lead; Link; Maintenance; Mammals; Mediating; Microbe; Modeling; Molecular; Mus; Natural Immunity; Nature; Outcome; P-2; Parasites; Pathogenesis; Pathology; Pelvic Inflammatory Disease; Phagocytes; Porifera; Predisposition; Probability; Resistance; Resolution; Role; Sexually Transmitted Diseases; Sterility; Stimulus; Testing; Time; Tissues; Tropism; Vaccines; Virulence; Work; World Health; adaptive immunity; antimicrobial; cell type; co-infection; combat; cytokine; design; genital infection; health economics; in vivo; insight; killings; macrophage; member; microbial; novel; obligate intracellular parasite; pathogen; perforin 2; porin; promoter; response; success; tissue culture; transmission process

 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.

 描述（由申请人提供）：由细菌病原体介导的性传播疾病是全球人类健康的重大负担。沙眼衣原体仍然是美国最常见的可报告病例，感染可导致后遗症，如宫外孕、不孕症和盆腔炎。虽然获得性免疫对于在鼠模型中清除衣原体是必不可少的，但衣原体感染引起了与限制感染Ascension以及宿主组织病理学相关的强先天免疫应答。我们最近发现了一种名为穿孔素-2的新型先天免疫因子，它能够杀死多种细胞相关细菌。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。一种专性细胞内存在，如衣原体属。需要进化机制来逃避或绕过通常会中和入侵微生物的先天宿主防御。我们的初步数据表明，衣原体阻断P-2活性在允许的细胞，但易受P-2介导的杀伤在非允许的细胞，如巨噬细胞。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介导的杀伤的敏感性或抗性的分子机制。总的来说，我们试图了解宿主和细菌因素，显着影响感染的结果。这项研究将有助于通过研究一种重要的人类病原体的感染生物学和宿主免疫的一个新的认识和必要组成部分的整体gal。