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艾滋病毒感染的传播，并且淋病和衣原体的控制需要继续成为艾滋病毒控制计划的重要议程。此外，淋球菌和衣原体混合感染的高流行率可能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结果，很少有研究检查合并感染的生物学，也没有研究这些微生物在相同的粘膜环境中如何相互作用。这是对检查的生物学机制的增强共同感染，这一建议是针对。我们的研究表明，人类生殖道上皮细胞暴露于淋球菌和衣原体诱导释放促炎细胞因子，包括IL-1，IL-6和TNF-α，这可能会激活静止的T细胞，改变居民活化的T细胞和巨噬细胞的易感性，并招募免疫细胞的HIV-1感染的目标，从而增强HIV-1感染或复制。为了支持这一观点，我们提供了初步的数据，表明淋球菌LOS和培养上清液取自生殖道上皮细胞感染的C。沙眼诱发 HIV-1在潜伏感染的前单核细胞系U1中的表达。考虑到淋球菌和衣原体感染会增强艾滋病毒的感染或复制，预防淋球菌和衣原体感染的战略也应该对艾滋病毒-1的传播产生影响。一种这样的方法是开发用于阴道或直肠应用的局部杀微生物剂，其可以防止粘膜表面的侵入。 新的杀微生物剂或替代疗法的鉴定需要了解STI病原体在粘膜表面共感染期间的分子相互作用。为此，我们将评估粘膜固有免疫反应淋球菌和衣原体感染，使用人类细胞培养系统重要的生殖器和肠道，并确定是否在粘膜环境的变化增强HIV感染。具体目标是：1）根据通过TLR和TREM受体的接合产生细胞因子和防御素来表征淋球菌和衣原体对生殖道和肠上皮细胞、内皮细胞和树突细胞的入侵的先天免疫应答; 2）确定淋球菌和衣原体入侵刺激先天免疫应答对HIV-1感染静止和活化的T细胞和巨噬细胞的影响;（3）确定淋球菌和衣原体侵入上皮细胞时，先天免疫应答细胞因子和防御素表达所涉及的信号转导事件。

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.