Promotion of HIV-1 transinfection by Mycoplasma genitalium

描述（由申请方提供）：生殖支原体是一种感染男性和女性生殖道上皮细胞的性传播病原体。这种药物会在这些组织中引起强烈的炎症，并且感染可能是持久的。生殖器粘膜传播 HIV-1（HIV）在发炎组织中最有效地发生，因为存在促进HIV感染靶细胞的炎性细胞因子和其他介质。本建议的一个长期目标是了解M之间的关系。生殖器感染和艾滋病毒传播/传播。我们在此建议使用双室Transwell共培养模式来模拟生殖器粘膜微环境，使用汇合的上皮细胞单层（未感染或感染M.生殖器）在顶室，在半透膜上，淋巴样细胞代表宫颈-阴道粘膜的淋巴样细胞在底室。使用该系统，我们计划确定（a）是否阶梯剂量的M。粘膜上皮细胞的生殖器感染促进剂量依赖性HIV穿过上皮屏障的运动;（B）是否阶梯剂量的M.生殖器感染的细胞促进底部孔中树突状细胞（DC）的剂量依赖性非感染性HIV捕获，和（c）是否阶梯剂量的M.生殖器感染的细胞放大了这些DC以感染形式和剂量依赖性方式将其捕获的HIV转移到在底部孔中与它们共培养的靶向CD 4 + T细胞的程度。这项研究将是第一个直接问是否和如何本地M。生殖器感染放大了重要的粘膜HIV传播事件。如果M.生殖器被证明是该系统中艾滋病毒感染的有力促进者，这将对预防艾滋病毒性传播具有明确的意义。在公共卫生方面，M.生殖器感染和有效治疗感染，可能会大大减缓艾滋病毒在高危人群中的传播。 公共卫生相关性：生殖支原体是一种常见的细菌，可引起性传播疾病，如女性宫颈炎和男性尿道炎。在两种性别中，细菌感染粘膜上皮细胞。据推测，在宫颈上皮细胞被M感染的妇女中，对性传播HIV的易感性增加。生殖器因此，我们建议确定是否M。生殖器感染培养的上皮细胞可以促进与它们共培养的T细胞的HIV感染。这项研究将是第一个问是否M。生殖器感染促进艾滋病毒传播。如果是这样，那么有效的筛查和治疗M。生殖器可以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.