Complement and hormone receptor modulation during gonococcal cervical infection

描述(由申请人提供)：由于宫颈淋病奈瑟菌感染，女性容易发展为慢性的，通常是严重的后果。尽管临床数据表明女性淋球菌感染与荷尔蒙因素有关，但这一研究途径很少受到关注。我们的数据与这一观点是一致的，并证明了雌激素(E2)和孕酮(PG)在调节宫颈上皮淋球菌感染中的不同作用。本研究的目的是明确类固醇激素受体(SHR)在原代宫颈上皮细胞在生理浓度的雌二醇和前列腺素作用下对淋球菌感染的反应(S)中的作用。我们以前的数据表明，淋球菌性宫颈炎症的无症状性质可能部分归因于淋球菌通过补体受体3(CR3)促进侵袭的方式颠覆补体(C‘)替代途径的正常功能。然而，值得注意的是，类固醇激素(SHS)具有抗炎特性，这部分归因于它们的同源细胞受体作为转录因子和/或调节细胞刺激触发的信号级联反应的能力。在这方面，SHR被证明调节一些C‘蛋白的表达。这项建议的一个独特方面涉及到我们使用原代人类宫颈上皮(PEX)细胞来研究女性淋球菌疾病的临床相关性。CR3是淋球菌在体内和体外利用的主要受体，与宫颈相关并侵袭宫颈。虽然CR3存在于Pex细胞上，但它不存在于(人类)男性泌尿生殖道、小鼠女性生殖道的上皮细胞上，也不存在于永生化/恶性宫颈细胞系。因此，通过使用Pex细胞作为下女性生殖道的模型，我们已经能够揭示淋病奈瑟菌致病机制的一些方面，这些方面是女性感染所特有的，并且已经被其他模型系统所忽视。我们是唯一一个常规使用原代人类上皮细胞来研究淋球菌发病机制的实验室。此外，最近的数据表明，在永生化/恶性宫颈上皮中，SHR的表达缺失或严重下调，使得永生细胞系在阐明SHR功能方面的作用有限。因此，我们非常适合提供SHS对宫颈生物学和淋病发病机制的影响的详细分析。公共卫生相关性：本应用的重点是确定类固醇激素对原代宫颈上皮的影响(S)，从而确定对无症状淋球菌性宫颈炎的影响。拟议的研究是细菌发病机制的一个重要且未被充分研究的领域，并且直接适用于人类健康。

DESCRIPTION (provided by applicant): Women are prone to develop chronic, often severe, consequences as a result of cervical infection with Neisseria gonorrhoeae. Although clinical data indicate that there is a hormonal component to gonococcal infection in women, this avenue of study has received little attention. Our data are consistent with this idea and demonstrate distinct roles for estrogen (E2) and progesterone (Pg) in modulating gonococcal infection of cervical epithelia. The objective of this proposal is to define the role of steroid hormone receptors (SHRs) in the response(s) of primary cervical epithelia to gonococal infection under physiological concentrations of E2 and Pg. Our previous data suggest that the asymptomatic nature of gonococcal cervicitis may, in part, be attributed to the ability of gonococci to subvert the normal function of the alternative pathway of complement (C') in such a way to promote invasion via complement receptor 3 (CR3). However, it is also noteworthy that steroid hormones (SHs) exert anti-inflammatory properties, which are, in part, attributed to the ability of their cognate cellular receptors, to function as transcription factors and/or to modulate signaling cascades triggered with cell stimulation. In this regard, SHRs are shown to regulate the expression of some C' proteins. One unique aspect of this proposal relates to the clinical relevance of our use of primary human cervical epithelial (pex) cells to study gonococcal disease of women. CR3 is the primary receptor exploited by N. gonorrhoeae, in vivo and ex vivo, to associate with and invade the cervix. Although CR3 is present on pex cells, it is not present on the epithelium of the (human) male urogenital tract, the mouse female genital tract, nor immortalized/malignant cervical cell lines. Therefore, by using pex cells as a model of the lower female genital tract, we have been able to reveal aspects of N. gonorrhoeae pathogenesis that are specific to infection of women and that have been over-looked by the use of other model systems. We are the only laboratory routinely using primary human epithelial cells to study gonococcal pathogenesis. Additionally, recent data indicate that SHR expression is absent or severely down regulated in immortalized/malignant cervical epithelia, making immortal cell lines of limited utility in elucidation of SHR function. Thus we are uniquely suited to provide a detailed analysis of the affect of SHs on cervical biology and gonococcal pathogenesis. PUBLIC HEALTH RELEVANCE: The focus of this application is to define the effect(s) of steroid hormones on primary cervical epithelia and, thereby, the effect on asymptomatic gonococcal cervicitis. The proposed studies are an important and under-investigated area of bacterial pathogenesis and are directly applicable to the human health.