C. trachomatis increases transmission of HIV: mechanisms in the endocervix

描述(申请人提供)：感染了性传播病原体，包括沙眼衣原体，增加了艾滋病毒-1通过女性生殖道的传播。我们将研究沙眼衣原体通过人类子宫内膜增加HIV-1传播率的机制，这是这种病原体组合的主要进入部位。我们将建立我们的可极化的宫颈上皮体外模型，初步数据显示，在存在沙眼衣原体感染的情况下，宫颈上皮完整性下降，宫颈内HIV-1受体和辅受体的表达增加。我们建议研究沙眼衣原体D血清型对HIV-1上皮细胞进入、整合和产生性感染的三条可能途径的影响，2)从宫颈上皮顶端到基底面的上皮细胞进入和跨细胞传递，以及3)上皮细胞间HIV-1病毒粒子的细胞旁运输。在这些研究中，我们将确定沙眼衣原体相关的宫颈内细胞表面表达增加的详细机制，即HIV-1受体GalCer、CXCR4和CCR5。我们将研究宫颈细胞紧密连接成分(连环素、钙粘附素、粘附素和非粘附素)在我们记录的沙眼衣原体感染后宫颈完整性下降中的作用。 在缺乏针对沙眼衣原体和HIV-1的疫苗的情况下，有效的阴道杀菌剂可能是我们防止这些性传播感染的异性传播的最佳方法。为该项目开发的体外模型将成为未来合理的第一阶段测试阴道杀菌剂抗沙眼衣原体和HIV-1的新成分的平台，包括选择性雌激素受体调节剂(SERM)、Toll样受体调节剂和益生菌。 我们的沙眼衣原体和HIV-1双重感染的体外模型将是最先研究性传播病原体之间相互作用的模型之一。与其他性传播病原体的混合感染和重叠感染在艾滋病毒传播中的作用尚未得到充分研究。我们的双重感染模型可以开始填补这一空白，并可以作为模板，在其他生殖黏膜上皮部位开发类似的双重感染模型，包括直肠粘膜、阴道粘膜和宫颈外粘膜。 公共卫生相关性：感染常见的性病原体沙眼衣原体会增加艾滋病毒-1的异性传播。利用一个新的人宫颈上皮细胞体外模型，我们将研究沙眼衣原体对HIV-1与宫颈内皮细胞结合、进入宫颈内皮细胞、整合到上皮细胞基因组、上皮细胞跨细胞和细胞外转运的影响机制。这项R21的发现将为未来的R01资金提供一个平台，以合理地测试阴道杀菌成分对双重病原体感染及其局部毒性的作用。

DESCRIPTION (provided by applicant): Infections with sexually transmitted pathogens, including Chlamydia trachomatis, increase the transmission of HIV-1 across the female genital tract. We will study the mechanisms by which C. trachomatis specifically increases HIV-1 transmissibility across the human endocervix, the primary site of entry for this combination of pathogens. We will build upon our polarizable in vitro models for endocervical epithelia and preliminary data showing a decrease in epithelial integrity and an increase in endocervical HIV-1 receptor and co-receptor expression in the presence of C. trachomatis infection. We propose to investigate the effects of C. trachomatis serovar D on three potential pathways for epithelial transmission of HIV-1, including: 1) epithelial cell entry, integration and productive infection, 2) epithelial cell entry and transcytosis from the apical to basal surface of the endocervical epithelia and 3) paracellular transport of HIV-1 virions between epithelial cells. Within these investigations, we will define detailed mechanisms for C. trachomatis-associated increases in the endocervical cell surface expression the HIV-1 receptors GalCer, CXCR4 and CCR5. We will investigate the roles of endocervical cell tight junction components (catenin, cadherin, nectin and afadin) in our documented decrease in endocervical integrity upon infection with C. trachomatis. In the absence of vaccines against C. trachomatis and HIV-1, effective vaginal microbicides may be our best approach to the prevention of heterosexual spread of each of these sexually transmitted infections. The in vitro models developed for this project will serve as a platform for future rational phase 1 testing of novel components of vaginal microbicides against C. trachomatis and HIV-1, including selective estrogen receptor modulators (SERMs), toll-like receptor modulators and probiotics. Our in vitro models for dual infection with C. trachomatis and HIV-1 will be one of the first to allow the study of interactions between sexually transmitted pathogens. The role of co-infection and superinfection with other sexually-transmitted pathogens in HIV transmission is understudied. Our dual infection models can begin to fill this gap and can act as templates for the development of similar dual-infection models in other reproductive mucosal epithelial sites, including rectal mucosa, vaginal mucosa and ectocervical mucosa. PUBLIC HEALTH RELEVANCE: Infection with the common sexual pathogen, Chlamydia trachomatis, increases the heterosexual transmission of HIV-1. Using a novel in vitro model of the human endocervical epithelium, the site primarily implicated in C. trachomatis/HIV interactions, we will study the mechanisms behind the effects of C. trachomatis on HIV-1 binding to the endocervix, entry into the endocervix, integration into the genome of the epithelial cell, epithelial cell transcytosis and paracellular transport across the endocervical epithelium. The findings in this R21 will provide a platform for future R01 funding to rationally test vaginal microbicidal components against dual pathogen infections and their local toxicities.