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

描述（由申请人提供）：性传播病原体（包括沙眼衣原体）感染可增加HIV-1在女性生殖道的传播。我们将研究C.沙眼衣原体特异性地增加HIV-1通过人宫颈内膜的传播性，宫颈内膜是这种病原体组合的主要进入部位。我们将建立我们的子宫颈内上皮细胞的体外极化模型和初步数据，这些数据显示在C存在下，上皮完整性降低，子宫颈内HIV-1受体和辅助受体表达增加。沙眼感染我们建议研究C.沙眼衣原体血清型D对HIV-1的上皮传播的三种潜在途径的作用，包括：1）上皮细胞进入、整合和生产性感染，2）上皮细胞进入和从宫颈内上皮的顶端到基底表面的转胞吞作用和3）HIV-1病毒粒子在上皮细胞之间的细胞旁转运。在这些调查中，我们将定义详细的机制C。宫颈内膜细胞表面HIV-1受体GalCer、CXCR 4和CCR 5表达的沙眼相关增加。我们将研究宫颈内细胞紧密连接成分（连环蛋白、钙粘蛋白、连接蛋白和afadin）在我们记录的感染C.沙眼 在缺乏抗C.沙眼和HIV-1，有效的阴道杀微生物剂可能是我们预防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作为未来合理的阴道杀微生物剂新组分对C的1期试验的平台。沙眼和HIV-1，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。 我们在体外建立了C.沙眼和HIV-1的研究将是第一批允许研究性传播病原体之间相互作用的研究之一。与其他性传播病原体的合并感染和重复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，在其他生殖粘膜上皮部位，包括直肠粘膜，阴道粘膜和宫颈外粘膜的类似的双重感染模型的发展。 公共卫生相关性：感染常见的性病原体沙眼衣原体会增加HIV-1的异性传播。使用一种新的人子宫颈内上皮体外模型，主要涉及C。沙眼衣原体/HIV相互作用，我们将研究C.沙眼衣原体对HIV-1与宫颈内膜结合、进入宫颈内膜、整合到上皮细胞的基因组中、上皮细胞胞吞转运和跨宫颈内膜上皮的细胞旁转运的影响。R21的研究结果将为未来的R 01基金提供一个平台，以合理测试阴道杀微生物成分对双重病原体感染及其局部毒性的影响。

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.