MUCOSAL ENTRY PATHS USED BY STD PATHOGENS

更好地了解STD病原体使用的粘膜进入誓言将有助于设计局部杀菌剂，因为这些药剂必须阻止粘膜表面的传播。该项目将研究潜在的高传播易感性的途径、媒介和部位。细胞载体：精液中既含有游离的病毒粒子，也含有感染病毒的白细胞，它们可能作为媒介传播艾滋病毒和其他性传播疾病。小鼠阴道中沉积的白细胞在几小时内进入阴道上皮并迁移到区域淋巴结节。通过在小鼠身上的实验和体外系统，我们将研究细胞进入的相关决定因素。利用一个新开发的HIV感染细胞经阴道传播给Hu-PBL-SCID小鼠的模型，我们将把细胞进入的细节与HIV感染细胞向Hu-PBL-SCID小鼠的传播效率联系起来，我们将把细胞进入的细节与感染效率联系起来。通过活体研究，我们将测试男性白细胞是否进入女性宫颈阴道上皮。上皮微损伤为STD/HIV的传播开辟了一条重要途径。我们将研究在双方同意的人类性交中，在不同情况下微损伤的频率和程度，并测试可能预防或加剧它的因素。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。上呼吸道暴露：现在已知子宫收缩会将液体从阴道输送到上生殖道，通过这一途径，病原体和感染细胞可能会到达比阴道上皮更容易感染的上皮细胞。我们将使用超声检查来研究子宫对阴道液的摄取，重点是与月经周期、液体粘度相关的摄取变化，以及精液和精液成分的影响。我们将尝试使用粘液增稠润滑剂、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，因为它们只能保护那些已经充分投放的表面。以抗体为基础的杀微生物剂为生殖器的分布提供了独特的潜力，这种分布可能从上尿路延伸到外阴，特别是在反复非性交剂量之后。我们将在与项目2和项目3的具体目标相协调的实验中，研究阴道应用的人类抗体在女性中的分布范围。

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.