Promotion of HIV-1 transinfection by Mycoplasma genitalium

描述(申请人提供)：生殖支原体是一种性传播的病原体，感染男性和女性生殖道的上皮细胞。这种物质会在这些组织中引起强烈的炎症，感染可能会持续很长时间。鸡传染性支气管炎生殖器粘膜传播 HIV-1(HIV)最有效地发生在炎症组织中，因为存在炎症细胞因子和其他促进HIV感染靶细胞的介质。这项建议的一个长期目标是了解生殖支原体感染和艾滋病毒传播/传播之间的关系。我们建议使用双腔Transwell共培养模式来模拟生殖器-粘膜微环境，在顶腔中有融合的上皮细胞单层(未感染或感染生殖支原体)，覆盖在半透膜上，在底腔中淋巴样细胞代表宫颈-阴道粘膜的淋巴细胞。利用这一系统，我们计划确定：(A)阶梯剂量的生殖支原体感染粘膜上皮细胞是否促进剂量依赖的HIV跨越上皮屏障的移动；(B)阶梯剂量的生殖支原体感染细胞是否促进底部井中的树突状细胞(DC)捕获剂量依赖的非传染性HIV；以及(C)阶梯剂量的生殖支原体感染细胞是否放大这些DC以感染形式和剂量依赖的方式将捕获的HIV转移到与它们在底部井中共同培养的目标CD4+T细胞的程度。这项研究将是第一次直接询问当地生殖支原体感染是否以及如何放大一项重要的粘膜艾滋病毒传播事件。如果生殖支原体在这一系统中被证明是艾滋病毒感染的有力促进者，这将对预防艾滋病毒的性传播具有明显的影响。在公共卫生方面，对生殖支原体感染进行筛查，并对感染进行有效治疗，可以显著减缓艾滋病毒在高危人群中的传播。 与公共卫生相关：生殖支原体是一种常见细菌，可引起性传播疾病，如女性的子宫炎和男性的尿道炎。无论男女，这种细菌都会感染粘膜上皮细胞。据推测，宫颈上皮细胞感染生殖支原体的妇女对艾滋病毒的性传播易感性增加。因此，我们建议确定培养的上皮细胞感染生殖支原体是否能促进与其共同培养的T细胞感染HIV。这项研究将首次提出生殖支原体感染是否会促进艾滋病毒传播。如果是这样，那么对生殖支原体进行有效的筛查和治疗可能会减缓艾滋病毒在高危人群中的传播。

DESCRIPTION (provided by applicant): Mycoplasma genitalium is a sexually transmitted pathogen that infects epithelial cells of the male and female reproductive tracts. This agent causes intense inflammation in these tissues, and infections can be long-lasting. Genital-mucosal transmission of HIV-1 (HIV) occurs most efficiently in inflamed tissues because of the presence of inflammatory cytokines and other mediators that promote infection of HIV to target cells. A long term objective of this proposal is to understand the relationship between M. genitalium infection and HIV dissemination/transmission. We propose here to use a dual-chamber Transwell coculturing format to model the genital-mucosal microenvironment, with a confluent epithelial cell monolayer (uninfected or infected with M. genitalium) in the top chamber, over a semipermeable membrane, and lymphoid cells representing those of the cervical-vaginal mucosae in the bottom chamber. Using this system, we plan to determine (a) whether stepped doses of M. genitalium infection of the mucosal epithelial cells facilitate dose-dependent HIV movement across the epithelial barrier; (b) whether stepped doses of M. genitalium-infected cells promote dose- dependent noninfectious HIV capture by dendritic cells (DCs) in the bottom well, and (c) whether stepped doses of M. genitalium-infected cells amplify the extent to which these DCs transfer their captured HIV, in an infectious form and in a dose-dependent fashion, to target CD4+ T cells co-cultured with them in the bottom well. This study will be the first to ask directly whether and how local M. genitalium infection amplifies an important mucosal HIV transmission event. If M. genitalium proves to be a potent facilitator of HIV infection in this system, this will have clear implications for prevention of HIV sexual transmission. In the public health context, screening for M. genitalium infection, and effective treatment of infections, may significantly slow HIV spread in populations at risk. PUBLIC HEALTH RELEVANCE: Mycoplasma genitalium is a common bacterium that causes sexually transmitted diseases such as cervicitis in women and urethritis in men. In both sexes, the bacterium infects mucosal epithelial cells. It has been speculated that susceptibility to sexual HIV transmission is increased in women whose cervical epithelial cells are infected by M. genitalium. We therefore propose to determine whether M. genitalium infection of cultured epithelial cells can promote HIV infection of T cells cocultured with them. This study will be the first to ask whether M. genitalium infection promotes HIV transmission. If it does, then effective screening and treatment for M. genitalium may slow HIV spread in populations at risk.