Bacterial STI and Innate Immunity in HIV Susceptibility

描述(由申请人提供)：流行病学和临床研究提供了强有力的证据，表明淋球菌和衣原体感染促进了艾滋病毒感染的传播，控制淋病和衣原体需要继续放在艾滋病毒控制计划的议程上。此外，淋球菌和衣原体混合感染的高流行率可能会进一步增加艾滋病毒传播的风险。然而，尽管有这些临床观察，很少有研究研究联合感染的生物学，也没有研究这些微生物在同一粘膜环境中可能如何相互作用。这项建议是针对增强合并感染的生物学机制的检查。我们的研究表明，人生殖道上皮细胞暴露于淋球菌和衣原体后，可以诱导包括IL-1、IL-6和TNF-α在内的促炎细胞因子的释放，这些细胞因子可能激活静止的T细胞，改变驻留激活的T细胞和巨噬细胞的易感性，并招募作为HIV-1感染靶点的免疫细胞，从而促进HIV-1的感染或复制。为了支持这一概念，我们提供的初步数据表明，淋球菌LO和从感染沙眼衣原体的生殖道上皮细胞中提取的培养上清可诱导 潜伏感染的前单核细胞株U1中HIV-1的表达。鉴于淋病和衣原体感染会增加艾滋病毒感染或复制，预防淋病和衣原体感染的战略也应对艾滋病毒-1传播产生影响。一种这样的方法是开发用于阴道或直肠的局部杀菌剂，可以防止粘膜表面的入侵。识别新的杀菌剂或替代疗法需要了解STI病原体在黏膜表面合并感染期间的分子相互作用。为此，我们将使用生殖器和肠道中重要的人类细胞培养系统来评估粘膜对淋球菌和衣原体感染的先天免疫反应，并确定粘膜环境的变化是否会增强艾滋病毒感染。其具体目的是：1)通过TLR和TREM受体的结合，从细胞因子和防御素的产生来表征淋球菌和衣原体对生殖道和肠道上皮细胞、内皮细胞和树突状细胞入侵的天然免疫反应；2)确定淋球菌和衣原体入侵对静止和激活的T细胞和巨噬细胞感染HIV-1的影响；3)确定淋球菌和衣原体入侵上皮细胞时天然免疫应答细胞因子和防御素表达的信号转导事件。

DESCRIPTION (provided by applicant): Epidemiologic and clinical studies provide strong evidence that gonococcal and chlamydial infections facilitate the transmission of HIV infection and that control of gonorrhea and chlamydia needs to remain high on the agenda of HIV control programs. In addition, the high prevalence of gonococcal and chlamydial co-infection may further increase the risk of HIV transmission. Yet despite these clinical observations, few studies have examined the biology of co-infection nor how these microbes might interact when in the same mucosal environment. It is toward the examination of the biological mechanism of enhancement of co-infection that this proposal is directed. Our studies have shown that exposure of human reproductive tract epithelial cells to gonococci and chlamydia induced the release of proinflammatory cytokines including IL-1, IL-6, and TNF-alpha, which may activate quiescent T cells, alter susceptibility of resident activated T cells and macrophages, and recruit immune cells that are targets for HIV-1 infection thereby enhancing HIV-1 infection or replication. In support of this concept, we provide preliminary data which indicates that gonococcal LOS and culture supernatants taken from reproductive tract epithelial cells infected with C. trachomatis induced HIV-1 expression in the latently-infected promonocytic cell line U1. Given that gonococcal and chlamydial infections enhance HIV infection or replication, strategies that prevent gonococcal and chlamydial should have an impact on HIV-1 transmission as well. One such approach is the development of topical microbicides for vaginal or rectal application that could prevent the invasion at mucosal surfaces. Identification of novel microbicides or alternative therapeutics requires an understanding of the molecular interactions of STI pathogens during co-infection at mucosal surfaces. To this end, we will evaluate the mucosal innate immune response to gonococcal and chlamydial infection using human cell culture systems important in the genital and intestinal tract and determine whether changes in the mucosal environment enhance HIV infection. The Specific Aims are: 1) to characterize the innate immune response to invasion of reproductive tract and intestinal epithelial, endothelial, and dendritic cells by gonococci and chlamydia in terms of the production of cytokines and defensins through engagement of TLR and TREM receptors; 2) to determine the effect of stimulation of innate immune responses by gonococcal and chlamydial invasion on HIV-1 infection of quiescent and activated T cells and macrophages; 3) to define the signal transduction events involved in the expression of innate immune response cytokines and defensins in response to invasion of epithelial cells by gonococci and chlamydia.