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.

描述（由申请人提供）：即使通过病毒大小的物体，女性生殖道的粘液分泌也极难穿透。那么为什么这些障碍有时无法预防性传播病原体？我们的试点数据表明，某些病原体太大而无法穿透粘液网状间距（孔径），并且粘液还会在达到目标细胞之前捕获一些病原体，例如飞胶。相反，异常粘液可能不会那么保护。大约3个女性患有细菌性阴道病（BV），艾滋病毒和其他病毒，细菌和原生动物病原体感染的风险> 2-6倍。 BV是阴道菌群的多菌血性过度生长，可消耗健康的乳酸杆菌，将阴道粘液转化为水性分泌，并部分消除了阴道的酸度。我们已经开发了粘液穿透颗粒（MPP），这些颗粒揭示了新鲜人类样品中的粘液网状间隔。因此，我们可以通过空间闭塞（病原体大小>网格间隔）和/或被粘附捕获的病原体在离体生殖器粘液中放慢的病原体。我们的试点观察结果表明，具有健康阴道菌群的妇女的天然（酸性）宫颈阴道粘液粘附于HPV，HIV和HSV。但是，如果用NaOH部分中和以模仿BV的中和作用，则HIV和HSV可以穿透这种粘液屏障。我们的总体假设是，具有健康阴道菌群女性的粘液分泌具有高度保护性的病原体渗透，但是BV女性中这种保护大大减少了。为了测试这一点，AIM 1将扩展我们的试点观察结果，并包括所有通常传播性病病原体的粘液分泌物：遗传粘液，健康的子宫颈阴道粘液，BV分泌和精液。我们将使用多个粒子跟踪和MPP来表征这些生殖器分泌物在纳米长至微长度尺度​​上经历的细分粘弹性和保护性的粘弹性。 AIM 2将确定可以阻止或延缓主要性病病原体（HIV，HSV，HPV，N。Gono​​rrhoeae和C. trachomatis）的分泌物，以及迅速渗透的分泌物。我们还将确定各种人分泌物中每种病原体所经历的确切粘度和弹性。这将为每种病原体经历的障碍程度提供重要的定量。综上所述，AIM 1和2的结果还将在每个分泌物中区分处于空间被阻塞的病原体和被困的粘合剂。 AIM 3将研究乳酸和乳酸阴离子的作用，从而导致粘液捕获性病病原体。我们的试点结果表明，乳酸特异性改变了HIV和HSV的表面，这可能有助于解释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如何增加对广泛的病毒，细菌和原生动物病原体渗透的敏感性。结果还可以支持创建使用乳酸来帮助防止BV并增强粘液分泌的保护作用的新方法 公共卫生相关性：与患有细菌性阴道病（BV）的女性相比，患有艾滋病毒，HSV，HPV和几种性质细菌和原生动物的艾滋病毒，HSV，HPV和几种性病细菌和原生动物的风险明显较小。不幸的是，只有少数女性（<40％）具有健康的阴道菌群，在任何给定时间，大约有3个女性患有BV。该项目将有助于揭示健康的阴道菌群如何帮助防御感染以及BV如何增加对感染的敏感性；结果可能会支持开发阴道产物和杀生物，从而增强阴道乳酸的广泛保护作用。