The role of Perforin-2 in Chlamydia pathogenesis

Perforin-2 在衣原体发病机制中的作用

基本信息

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
项目类别：
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

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

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项目摘要

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（由适用提供）：细菌病原体介导的性传播疾病代表了全世界人类健康的重大燃烧。沙眼衣原体仍然是美国最普遍的病例，感染可能导致后遗症，例如生态妊娠，不育和骨盆炎性疾病。虽然适应性免疫学对于在鼠模型中清除衣原体至关重要，但衣原体感染引起了一种与限制感染和宿主组织病理学的限制假设相关的稳健的先天免疫响应。我们最近确定了一种称为Perforin-2的新型先天免疫因子，能够杀死广泛的细胞相关细菌。这些观察结果可能使P-2是打击细菌感染的关键宿主因子。像衣原体属的典型的细胞内存在一样。必须进化机制，以逃避或规避通常会中和入侵微生物的先天宿主防御措施。我们的初步数据表明，衣原体在宽敞的细胞中阻断P-2活性，但易受P-2介导的巨噬细胞（如巨噬细胞）中介导的杀戮。我们将利用体外组织培养和体内鼠感染模型，以阐明管理衣原体对P-2介导的杀伤的敏感性或抗性的分子机制。总体而言，我们试图了解显着影响感染结果的宿主和细菌因素。这项研究将通过研究重要的人类病原体的感染生物学以及宿主免疫的新成分和重要组成部分来促进整体GAL。