The affect of hormones and oxygen-limitation on gonococcal pathophysiology

描述（由申请人提供）：临床数据表明，女性淋球菌感染有激素成分;然而，类固醇激素和氧气限制对淋球菌感染的影响是一个研究不足的重要研究领域。我们的长期目标是阐明淋球菌和宫颈上皮之间发生的动态相互作用，这有助于妇女的无症状疾病，最终目标是改善妇女的健康。本申请的目的是提供淋球菌如何响应类固醇激素，以及氧气限制（缺氧），将发生在体内，在淋球菌感染期间的宫颈微环境中的详细了解。我们的中心假设是，在体内，淋菌性宫颈炎是由氧气限制以及阴道分泌物引起的淋球菌和宫颈上皮的变化所控制的。无症状的宫颈炎是导致妇女倾向于发展慢性淋球菌病后遗症的主要因素，这转化为大量相关的医疗费用。因此，拟议的研究的理由是，在月经周期的背景下，更好地了解淋球菌的发病机制是必不可少的未来发展的治疗战略，以打击淋球菌疾病，并提供框架，改善妇女的健康。因此，拟议的研究直接适用于NIH的使命的一部分，即发展基础知识，减少人类疾病的负担。在强有力的初步数据的指导下，将追求两个特定的目标来检验这一假设：1）定义N.响应于类固醇激素和氧限制的淋病表达谱;和2）确定类固醇激素和氧限制对原代人宫颈上皮细胞模型中补体-淋球菌相互作用的影响。在目标1，我们将确定淋球菌成分，可能有助于淋球菌疾病在体内。这些分子的一个子集将被进一步分析，以确定它们对促进宫颈疾病的潜在贡献。补体的产生对类固醇激素有反应，在介导宫颈感染中起关键作用。因此，目的2包括分析以进一步确定在体内可能遇到的条件下补体-淋球菌相互作用。我们还将表征一个假定的淋球菌补体结合蛋白，NGO 0033。各种细胞，分子和生物化学技术将被用来完成我们的具体目标的目标。这些调查是第一次检查如何结合，变量，生理水平的类固醇激素和缺氧可能通过使用一个主要的，人类的，上皮细胞模型，调节细菌的发病机制，因此，是创新的。拟议的研究是重要的，因为它预计将产生非常有意义的数据，关于淋球菌如何应对外源性压力（即。e.激素、补体和/或氧限制）。公共卫生相关性：妇女更容易发展慢性，往往是严重的，由于宫颈感染淋病奈瑟氏菌，导致淋病的细菌的后果。本申请的重点是确定类固醇激素和氧限制对淋球菌疾病的影响。拟议的研究是细菌致病机理的一个重要和未充分研究的领域，适用于人类健康。

DESCRIPTION (provided by applicant): Clinical data indicate that there is a hormonal component to gonococcal infection in women; however, the effect of steroid hormones and oxygen limitation to gonococcal infection is an under-investigated, important, area of study. Our long-term goal is to elucidate the dynamic interactions, occurring between the gonococcus and the cervical epithelium, which contribute to asymptomatic disease in women, with the ultimate goal of improved women's health. The intent of this application is to provide a detailed understanding of how gonococci respond to steroid hormones, as well as to oxygen limitation (hypoxia), as would occur, in vivo, within the cervical microenvironment during gonococcal infection. It is our central hypothesis that, in vivo, gonococcal cervicitis is governed by oxygen limitation as well as by hormone-induced changes to the gonococcus and to the cervical epithelium. Asymptomatic cervicitis is the primary factor contributing to the propensity of women to develop chronic gonococcal disease sequelae, which translates into substantial associated health cost. Therefore, the rationale for the proposed studies is that a greater understanding of gonococcal pathogenesis in the context of the menses cycle is imperative to the future development of therapeutic strategies to combat gonococcal disease and to provide the framework for improved women's health. Thus, the proposed research is directly applicable to that part of the NIH's mission that pertains to the development of fundamental knowledge that will reduce the burden of human illness. Guided by strong preliminary data, two specific aims will be pursued to test this hypothesis: 1) Define changes occurring during cervical infection in the N. gonorrhoeae expression profile in response to steroid hormones and oxygen limitation; and 2) Define the effect of steroid hormones and oxygen limitation on the complement-gonococcus interaction in a primary human cervical epithelial cell model. Within Aim 1, we will identify gonococal constituents that are likely to contribute to gonococcal disease in vivo. A subset of these molecules will be analyzed further to define their potential contribution to promoting cervical disease. Complement production is responsive to steroid hormones and plays a critical role in mediating cervical infection. Thereby, Aim 2 comprises analyses to further define the complement-gonococcus interaction under conditions likely to be encountered in vivo. We will also characterize a putative gonococcal complement binding protein, NGO0033. A variety of cellular, molecular, and biochemical techniques will be used to complete the objectives of our Specific Aims. These investigations are the first to examine how combined, variable, physiological levels of steroid hormones and hypoxia potentially modulate bacterial pathogenesis by using a primary, human, epithelial cell model, and, thus, are innovative. The proposed research is significant because it is expected to generate exceedingly meaningful data regarding how gonococci respond to exogenous stresses (i. e. hormones, complement, and/or oxygen limitation) in the context of mucosal epithelial infection. PUBLIC HEALTH RELEVANCE: Women are more prone to develop chronic, often severe, consequences as a result of cervical infection with Neisseria gonorrhoeae, the bacterium that causes gonorrhea. The focus of this application is to define the effect of steroid hormones and oxygen limitation to gonococcal disease. The proposed studies are an important and under-investigated area of bacterial pathogenesis and are applicable to human health.