Role of CD8+ T cells in Reproductive Sequelae Induced by Chlamydia Infection

CD8 T 细胞在衣原体感染引起的生殖后遗症中的作用

• 批准号: 7874276
• 负责人: Ashlesh Krishna Murthy
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874276
• 关键词: Affect; Animal Model; Animals; Antigens; Applications Grants; Attention; B-Lymphocytes; Bacteria; Bacterial Sexually Transmitted Diseases; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Development; Ectopic Pregnancy; Evaluation; Female; Fertility; Genital system; Histopathology; Horns; Human; Immune; Immune response; Infection; Infertility; Inflammatory; Intervention; Kinetics; Lead; Mammalian Oviducts; Manuscripts; Mediating; Microscopic; Mus; Nude Mice; Pathogenesis; Pathologic; Pathology; Pelvic Inflammatory Disease; Preventive; Process; Production; Role; SCID Mice; Severe Combined Immunodeficiency; Source; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Woman; base; cell type; cytokine; mouse model; pathogen; prevent; public health relevance; reproductive

DESCRIPTION (provided by applicant): Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide. Untreated genital chlamydial infections cause serious sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. The mechanisms involved in the pathogenesis of chlamydial infections are not understood, and needs urgent attention to develop strategies to reduce the clinically highly relevant pathology induced by these infections. It is generally thought that the host immune response, primarily T cells, that are involved in clearance of the bacterium also cause collateral tissue damage and the pathological sequelae in the upper genital tract (UGT). We have recently found that mice depleted of CD8+ T cells display significantly reduced oviduct and uterine horn pathology, without a significant change in the kinetics of chlamydial clearance. Moreover, antigen-specific TNF-? production correlated with the development of chlamydial upper genital tract (UGT) pathology. An association between high levels of TNF-? production and chlamydial UGT pathology also has been suggested by other studies. Based on these results, we hypothesize that "Chlamydia-specific CD8? T cells mediate the upper genital tract pathology following primary genital chlamydial infection" and determine the role of TNF-? as an underlying mechanism. We will test this hypothesis by; (1) Examining the direct effect of adoptively transferred Chlamydia-specific CD8? T cells in the induction of chlamydial UGT pathology, including infertility, and (2) Examining the contribution of TNF-? as an underlying mechanism to the CD8+ T cell-mediated UGT pathology following primary genital chlamydial challenge. PUBLIC HEALTH RELEVANCE: Genital Chlamydia trachomatis infections lead to severe pathology in the upper genial tract including pelvic inflammatory disease, ectopic pregnancy, and infertility. We have observed that depletion of CD8+ T cells leads to significant reduction of chlamydial pathology in the mouse model of genital chlamydial infection. This proposal will further examine the contribution of CD8+ T cells in the induction of severe chlamydial upper genital tract pathologies, in an attempt to characterize a potential target for reduction of the clinically highly relevant pathologies. .

描述（由申请人提供）：沙眼衣原体是全球细菌性性传播疾病的主要原因。未经治疗的生殖器衣原体感染会导致严重的后遗症，如盆腔炎、宫外孕和不孕症。衣原体感染的发病机制尚不清楚，迫切需要关注制定策略，以减少这些感染引起的临床高度相关的病理。通常认为，参与细菌清除的宿主免疫应答（主要是T细胞）也会引起上生殖道（UGT）中的附带组织损伤和病理学后遗症。我们最近发现，小鼠耗尽的CD 8 + T细胞显示显着减少输卵管和子宫角的病理，没有显着变化的动力学衣原体清除。此外，抗原特异性TNF-？生产相关的衣原体上生殖道（UGT）病理的发展。高水平的TNF-？其他研究也提示了衣原体UGT病理学。基于这些结果，我们假设“衣原体特异性CD 8？T细胞介导原发性生殖道衣原体感染后的上生殖道病理，并确定TNF-？作为一种潜在的机制。我们将测试这一假设;（1）检查过继转移衣原体特异性CD 8？T细胞在诱导衣原体UGT病理，包括不孕症，和（2）检查TNF-？作为原发性生殖道衣原体感染后CD 8 + T细胞介导的UGT病理学的潜在机制。 公共卫生关系：生殖道沙眼衣原体感染导致上生殖道严重病变，包括盆腔炎、异位妊娠和不孕症。我们已经观察到，在生殖器衣原体感染的小鼠模型中，CD 8 + T细胞的耗竭导致衣原体病理学的显著减少。该提案将进一步研究CD 8 + T细胞在诱导严重衣原体上生殖道病理中的作用，试图表征减少临床高度相关病理的潜在靶点。.