Promotion of HIV-1 transinfection by Mycoplasma genitalium

生殖支原体促进 HIV-1 转染

基本信息

批准号：
8046371
负责人：
SUBRAMANIAN DHANDAYUTHAPANI
金额：
$ 18.38万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-17 至 2013-02-28
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：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。这种物质会引起这些组织的强烈炎症，并且感染可能会持续很长时间。生殖器粘膜传播 HIV-1 (HIV) 在发炎组织中最有效地发生，因为存在炎症细胞因子和其他促进 HIV 感染靶细胞的介质。该提案的长期目标是了解生殖支原体感染与艾滋病毒传播/传播之间的关系。我们在这里建议使用双室 Transwell 共培养格式来模拟生殖器粘膜微环境，在顶室中覆盖半透膜，汇合的单层上皮细胞（未感染或感染生殖支原体），以及代表这些细胞的淋巴细胞底部腔室中的宫颈阴道粘膜。使用该系统，我们计划确定（a）粘膜上皮细胞的生殖支原体感染的阶梯剂量是否促进剂量依赖性艾滋病毒跨上皮屏障的移动； (b) 渐进剂量的生殖支原体感染细胞是否促进底孔中树突状细胞 (DC) 剂量依赖性非感染性 HIV 捕获，以及 (c) 渐进剂量的生殖支原体感染细胞是否会放大捕获非感染性 HIV 的程度这些树突状细胞以感染形式和剂量依赖性方式将捕获的艾滋病毒转移到与底孔共培养的 CD4+ T 细胞上。这项研究将首次直接询问局部生殖支原体感染是否以及如何放大重要的粘膜艾滋病毒传播事件。如果生殖支原体被证明是该系统中艾滋病毒感染的有效促进者，这将对预防艾滋病毒性传播产生明显的影响。在公共卫生方面，筛查生殖支原体感染并有效治疗感染可能会显着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细菌，可引起性传播疾病，例如女性宫颈炎和男性尿道炎。无论男女，该细菌都会感染粘膜上皮细胞。据推测，宫颈上皮细胞被生殖支原体感染的女性，艾滋病毒性传播的易感性会增加。因此，我们建议确定培养的上皮细胞的生殖支原体感染是否可以促进与其共培养的 T 细胞的 HIV 感染。这项研究将首次探讨生殖支原体感染是否会促进艾滋病毒传播。如果确实如此，那么对生殖支原体的有效筛查和治疗可能会减缓艾滋病毒在高危人群中的传播。