Pathogen trapping by genital mucus secretions

生殖器粘液分泌物捕获病原体

• 批准号: 7768486
• 负责人: RICHARD CONE
• 金额: $ 34.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768486
• 关键词: AIDS/HIV problem; Abbreviations; Acidity; Adhesions; Adhesives; Amplifiers; Anaerobic Bacteria; Anions; Bacteria; Bacterial Vaginosis; Belief; Blood; Bolus Infusion; Cells; Cervical; Characteristics; Charge; Chlamydia trachomatis; Data; Development; Diffuse; Dose; Elasticity; Epidemiology; Eye; Female; Gastrointestinal tract structure; Gel; Genital system; Grant; HIV; HIV Infections; Hour; Human; Human Papillomavirus; Infection; Injection of therapeutic agent; Label; Lactic acid; Lactobacillus; Length; Liquid substance; Lung; Measurement; Measures; Mediating; Methods; Minority; Modeling; Monkeys; Mono-S; Motion; Mucous Membrane; Mucous body substance; Neisseria gonorrhoeae; Nose; Obstruction; Ovulation; Paper; Penetration; Play; Predisposition; Property; Protozoa; Risk; Role; Sampling; Seminal Plasma; Seminal fluid; Simplexvirus; Skin; Stream; Surface; Techniques; Testing; Time; Tissues; Vagina; Viral; Virus; Viscosity; Woman; experience; genital secretion; interest; microbicide; nano; nanoparticle; nanoscale; pandemic disease; particle; pathogen; prevent; protective effect; public health relevance; reproductive; vaginal lactobacilli; vaginal microbicide; viscoelasticity

DESCRIPTION (provided by applicant): Mucus secretions from the female reproductive tract are extremely difficult to penetrate even by virus-sized objects. Why then do these barriers sometimes fail to protect against sexually transmitted pathogens? Our pilot data suggests some pathogens are too large to penetrate mucus mesh-spacing (pore size), and mucus also traps some pathogens like fly-paper before they can reach target cells. In contrast, abnormal mucus may not be so protective. About 1 in 3 women have bacterial vaginosis (BV), and they are at >2-6-fold increased risk of infection by HIV and other viral, bacterial, and protozoan pathogens. BV is a polymicrobial overgrowth of vaginal flora that decimates healthy lactobacilli, transforms vaginal mucus to a watery secretion, and partially eliminates the acidity of the vagina. We have developed mucus penetrating particles (MPP) that reveal the mucus mesh-spacing in fresh human samples. We can thus identify pathogens that are slowed in ex vivo genital mucus fluids by steric occlusion (pathogen size > mesh-spacing) and/or trapped by adhesion. Our pilot observations indicate native (acidic) cervicovaginal mucus from women with healthy vaginal flora adhesively traps HPV, HIV, and HSV. But, if partially neutralized with NaOH to mimic neutralizing actions of BV, HIV and HSV can penetrate this mucus barrier. Our overall hypothesis is that mucus secretions from women with healthy vaginal flora are highly protective against pathogen penetration, but that this protection is greatly diminished in women with BV. To test this, Aim 1 will extend our pilot observations and include all mucus secretions through which STD pathogens are usually transmitted: endocervical mucus, healthy cervicovaginal mucus, BV secretions, and semen. We will use multiple particle tracking and MPP to characterize the meshspacing and protective viscoelastic properties of these genital secretions at the nano- to micro- length scales experienced by pathogens. Aim 2 will identify the secretions that can block or retard penetration by major STD pathogens (HIV, HSV, HPV, N. gonorrhoeae and C. trachomatis), and secretions that are rapidly penetrated. We will also determine the exact viscosity and elasticity experienced by each pathogen in the various human secretions. This will provide important quantitation of the extent of impediment each pathogen experiences. Taken together, the results from Aims 1 & 2 will also distinguish pathogens blocked sterically, and those trapped adhesively, in each secretion. Aim 3 will investigate the roles of lactic acid, and lactate anions, in causing STD pathogens to be trapped by mucus. Our pilot results show lactic acid specifically alters the surfaces of HIV and HSV, and this may help explain how they are trapped by healthy mucus. This project will likely clarify how abnormal mucus secretions caused by BV increase susceptibility to penetration of a broad range of viral, bacterial, and protozoal pathogens. The results may also support the creation of new methods that use lactic acid to help prevent BV and enhance the protective effects of mucus secretions PUBLIC HEALTH RELEVANCE: Women with healthy vaginal flora (lactobacilli) are at markedly less risk of HIV, HSV, HPV, and several STD bacteria and protozoa than women with bacterial vaginosis (BV). Unfortunately, only a minority of women (<40%) have healthy vaginal flora and at any given time about 1 in 3 women have BV. This project will help reveal how healthy vaginal flora helps protect against infection and how BV increases susceptibility to infections; the results will likely support developing vaginal products and microbicides that reinforce the broad- spectrum protective actions of vaginal lactic acid.

性状（由申请方提供）：即使是病毒大小的物体也极难穿透女性生殖道的粘液分泌物。那么，为什么这些屏障有时不能防止性传播病原体呢？我们的试验数据表明，一些病原体太大，无法穿透粘液网间距（孔径），粘液也会在到达靶细胞之前捕获一些病原体，如蝇纸。相比之下，异常的粘液可能没有那么好的保护作用。大约三分之一的女性患有细菌性阴道病（BV），并且他们感染HIV和其他病毒，细菌和原生动物病原体的风险增加>2-6倍。BV是一种阴道植物群的多微生物过度生长，其大量杀死健康的乳酸杆菌，将阴道粘液转化为水性分泌物，并部分消除阴道的酸性。我们已经开发了粘液穿透颗粒（MPP），揭示了新鲜人体样本中的粘液网格间距。因此，我们可以鉴定在离体生殖器粘液中通过空间闭塞（病原体大小>网格间距）减慢和/或通过粘附捕获的病原体。我们的初步观察表明，来自健康阴道植物群的女性的天然（酸性）宫颈阴道粘液可捕获HPV、HIV和HSV。但是，如果用NaOH部分中和以模拟BV的中和作用，HIV和HSV可以穿透这种粘液屏障。我们的总体假设是，具有健康阴道植物群的女性的粘液分泌物对病原体渗透具有高度保护作用，但这种保护作用在BV女性中大大减弱。为了验证这一点，目标1将扩大我们的试点观察，包括所有的粘液分泌物，性病病原体通常通过传播：宫颈粘液，健康的宫颈阴道粘液，BV分泌物和精液。我们将使用多粒子跟踪和MPP来表征这些生殖器分泌物在病原体所经历的纳米到微米长度尺度上的网格间距和保护性粘弹性。目的2将确定可以阻断或延迟主要STD病原体（HIV、HSV、HPV、N.淋球菌和C.沙眼）和快速渗透的分泌物。我们还将确定每种病原体在各种人类分泌物中所经历的确切粘度和弹性。这将为每种病原体经历的阻碍程度提供重要的定量。总的来说，来自目标1和2的结果还将区分在每种分泌物中空间上被阻断的病原体和空间上被捕获的病原体。目的3将研究乳酸和乳酸阴离子在导致STD病原体被粘液捕获中的作用。我们的试验结果表明，乳酸特异性地改变了HIV和HSV的表面，这可能有助于解释它们如何被健康的粘液捕获。该项目可能会阐明BV引起的异常粘液分泌物如何增加对广泛的病毒、细菌和原生动物病原体渗透的易感性。该结果也可能支持创建使用乳酸帮助预防BV和增强粘液分泌物的保护作用的新方法 公共卫生关系：阴道植物群（乳酸杆菌）健康的妇女感染HIV、HSV、HPV和几种STD细菌和原虫的风险明显低于细菌性阴道病（BV）妇女。不幸的是，只有少数女性（<40%）具有健康的阴道植物群，并且在任何给定时间，约三分之一的女性患有BV。该项目将有助于揭示健康的阴道植物群如何帮助预防感染，以及BV如何增加对感染的易感性;结果将可能支持开发阴道产品和杀微生物剂，加强阴道乳酸的广谱保护作用。