MUCOSAL ENTRY PATHS USED BY STD PATHOGENS

更好地了解性病病原体使用的粘膜进入誓词将有助于设计局部杀微生物剂，因为这些制剂必须阻断粘膜表面的传播。本项目将研究潜在高传播易感性的途径、媒介和位点。细胞载体：精液中既含有游离病毒粒子，也含有病毒感染的白细胞，它们可能作为媒介介导艾滋病毒和其他性传播疾病的传播。在小鼠阴道内沉积的白细胞进入阴道上皮，并在几小时内迁移到局部淋巴结。通过小鼠实验和体外系统，我们将研究细胞进入的相关决定因素。利用新近开发的HIV感染细胞阴道传播到hu-PBL-SCID小鼠的模型，我们将把细胞进入的细节与HIV感染细胞在hu-PBL-SCID小鼠中的有效传播联系起来，我们将把细胞进入的细节与感染的效率联系起来。通过体内研究，我们将测试男性白细胞是否进入女性宫颈阴道上皮。上皮微创伤开辟了性病/艾滋病传播的重要途径。我们将研究在双方同意的人类性交中不同情况下微创伤的频率和程度，并测试可能预防或加剧微创伤的因素。这些结果将与小鼠HSV-2和HIV/SCID模型中类似创伤引起的易感性增加进行比较。上生殖道暴露：现在已知子宫收缩可将液体从阴道输送到上生殖道，病原体和受感染细胞可通过这一途径到达比阴道上皮更敏感的上皮。我们将利用超声技术研究子宫对阴道液体的摄取，重点关注与月经周期、液体粘度以及精液和精液成分的影响有关的摄取变化。我们将尝试使用黏液增稠润滑剂，通过插入宫颈屏障和药物手段来阻止子宫摄取（和暴露）。局部杀微生物剂的有效分布对其有效性至关重要，因为它们只能保护已充分送达的表面。基于抗体的杀微生物剂具有独特的生殖分布潜力，可从上尿道延伸到外阴，特别是在反复非性交剂量后。我们将在实验中研究女性阴道应用的人类抗体的分布程度，这些实验将与项目2和3的具体目标相协调。

A better understanding of the mucosal entry oaths used by STD pathogens will aid in designing topical microbicides since these agents must block transmission at mucosal surfaces. This project will study pathways, vectors, and sites of potential high transmission susceptibility. Cell vectoring: Semen contains both free virions, and virus-infected leukocytes that may act as vectors mediating transmission of HIV and other STDs. Leukocytes deposited in the vaginas of mice enter the vaginal epithelium and migrate to regional lymph nodes within a few hours. With experiments in mice, and a in vitro system, we will study relevant determinants of cell entry. Using a newly developed model of vaginal transmission by HIV-infected-cells to hu-PBL-SCID mice, we will correlate details of cell entry with efficiency transmission by HIV- infected-cells to hu-PBL-SCID mice, we will correlate details of cell entry with efficiency of infection. With in vivo studies, we will test if male leukocytes enter female cervicovaginal epithelia. Epithelial microtrauma opens a significant pathway for STD/HIV transmission. We will study the frequency and extent of microtrauma under various circumstances in consensual human coitus, and test factors that may prevent or exacerbate it. These results will be compared with the increase in susceptibility caused by comparable trauma in the mouse HSV-2 and HIV/SCID models. Upper tract exposure: Uterine contractions are now known to transport fluids from the vagina to the upper genital tract, a route whereby pathogens and infected-cells may reach epithelia more susceptible than vaginal epithelium. Using sonography we will study this uterine uptake of vaginal fluids, focusing on variation in uptake associated with menstrual cycle, fluid viscosity, and the effect of semen and semen constituents. We will attempt to block uterine uptake (and exposure) using mucus- thickening lubricants, by interposing cervical barriers, and by pharmacologic means. Effective distribution of topical microbicides is critical for their effectiveness since they can only protect those surface to which they have been adequately delivered. Antibody-based microbicides offer unique potential for genital distribution that may extend from the upper tract to vulva, particularly after repeated non-coital dosing. We will study the extent of distribution of vaginally applied human antibodies in women, in experiments that will coordinate with the Specific Aims of Projects 2 and 3.