Pathogensis of Chlamydial Infection

衣原体感染的发病机制

基本信息

批准号：
10014076
负责人：
HARLAN D CALDWELL
金额：
$ 156.47万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10014076
关键词：
Affect Antibiotic Therapy Attenuated Live Virus Vaccine Chlamydia Chlamydia Infections Chlamydia trachomatis Cytosol Disease Ectopic Pregnancy Epithelial Cells Female Fibrinogen Functional disorder Future Gene Proteins Goals Host Defense Immune response Immunity Infection Inflammasome Inflammatory Interleukin-1 alpha Interleukin-1 beta Investigation Lipoprotein (a)Lipoproteins Logic Mammalian Oviducts Membrane Membrane Proteins Modeling Molecular Mus Mutation Natural Immunity Pathogenicity Pathology Pathway interactions Pattern Pelvic Inflammatory Disease Phagocytes Pharmacotherapy Plasmids Prevention Public Health Research Sexually Transmitted Diseases Testing Trachoma Vaccines Virulence Factors Woman Work base chronic infection design diagnostic screening health management mouse model pathogen prevent reproductive tract tubal infertility urogenital tract

Affect Antibiotic Therapy Attenuated Live Virus Vaccine Chlamydia Chlamydia Infections Chlamydia trachomatis Cytosol Disease Ectopic Pregnancy Epithelial Cells Female Fibrinogen Functional disorder Future Gene Proteins Goals Host Defense Immune response Immunity Infection Inflammasome Inflammatory Interleukin-1 alpha Interleukin-1 beta Investigation Lipoprotein (a)Lipoproteins Logic Mammalian Oviducts Membrane Membrane Proteins Modeling Molecular Mus Mutation Natural Immunity Pathogenicity Pathology Pathway interactions Pattern Pelvic Inflammatory Disease Phagocytes Pharmacotherapy Plasmids Prevention Public Health Research Sexually Transmitted Diseases Testing Trachoma Vaccines Virulence Factors Woman Work base chronic infection design diagnostic screening health management mouse model pathogen prevent reproductive tract tubal infertility urogenital tract

展开

项目摘要

Chlamydia trachomatis infection of oculogenital epithelial cells causes blinding trachoma and sexually transmitted disease (STD); diseases that affect hundreds of millions of people world-wide. Infection of women has serious post-infection sequalae such as pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. A pathognomonic feature of these diseases is the inability of the host to generate an adequate protective immune response resulting in multiple episodes of re-infection or persistent infection that leads to damaging inflammatory disease of unknown pathophysiology. Current public health management of trachoma and STD is based on mass drug treatment or aggressive diagnostic screening and antibiotic treatment; respectively, that unfortunately have been largely ineffective. Effective control of trachoma and chlamydial STD requires a vaccine. The overall goal of our work is to understand the pathogenic mechanisms by which chlamydia evade host defenses that allow for the establishment of chronic infection and damaging inflammatory disease. Our logic is that a better understanding of the pathobiology of chlamydial infection and disease will be important to the design of new effective vaccines for the prevention of trachoma and STD. To this end, we have used a female mouse model of urogenital tract infection and focused our investigations on the study of two chlamydial virulence factors; (i) the C. trachomatis inclusion membrane protein CT135, and (ii) the C. trachomatis plasmid. We found CT135 functions in the evasion of host innate immunity by exporting outer membrane lipoprotein, a pathogen associated molecular pattern molecule, from the chlamydial inclusion to the host cytosol. CT135 exported lipoprotein specifically targets and activates the MyD88 non-canonical inflammasome pathway of phagocytes resulting in the secretion of IL1-alpha and IL1-beta that subsequently drives damaging inflammatory oviduct pathology. Moreover, we found that the chlamydial plasmid functions in the establishment of persistent infection of the female genital tract. Plasmid gene proteins 3 and 4 were found to be essential in establishing persistent infection. Future studies will design C. trachomatis vaccine strains that have been genetically modified to mutationally inactive CT135 and cured of the plasmid. These strains will be tested as live-attenuated vaccines to prevent chlamydial STD using the mouse genital tract model.

眼源性上皮细胞的沙眼衣原体感染会导致性沙眼瘤和性传播疾病（STD）；影响全球数亿人的疾病。女性感染患有严重的感染后序列，例如骨盆炎症性疾病，输卵管不育症和异位妊娠。这些疾病的病理特征是宿主无法产生足够的保护性免疫反应，导致多次感染或持续感染发作，从而导致损害未知病理生理学的炎症性疾病。当前对沙眼和性病的公共卫生管理基于大规模药物治疗或侵略性诊断筛查和抗生素治疗；不幸的是，这在很大程度上是无效的。有效控制沙眼和衣原体性病需要接种疫苗。我们工作的总体目标是了解衣原体逃避宿主防御的致病机制，从而允许建立慢性感染和破坏性炎症性疾病。我们的逻辑是，对衣原体感染和疾病的病理学有更好的了解对于设计新有效的疫苗以防止沙眼和性病很重要。为此，我们使用了泌尿生殖道感染的女小鼠模型，并将研究集中在研究两个衣原体毒力因子上。（i）沙眼链球菌包含膜蛋白CT135和（ii）沙眼梭状芽孢杆菌质粒。我们发现CT135通过导出从衣原体包含到宿主细胞质的，通过导出一种与病原体相关的分子模式分子出口外膜脂蛋白（一种相关的分子分子分子）来逃避宿主先天免疫。 CT135导出的脂蛋白特异性靶向并激活吞噬细胞的MYD88非典型炎症途径，从而导致IL1-Alpha和IL1-β的分泌，随后驱动了损害炎症性卵巢病理学。此外，我们发现衣原体质粒在建立女性生殖道的持续感染中起作用。发现质粒基因蛋白3和4在建立持续感染中至关重要。未来的研究将设计经过遗传改性为突变无活性CT135并固化质粒的沙眼型疫苗菌株。这些菌株将被测试为实时销售疫苗，以防止使用小鼠生殖道模型进行衣原体性病。