Complement and hormone receptor modulation during gonococcal cervical infection

描述（由申请人提供）：由于宫颈感染淋病奈瑟菌，妇女容易出现慢性，通常是严重的后果。虽然临床数据表明，有激素成分的淋球菌感染的妇女，这方面的研究很少受到重视。我们的数据与这一观点一致，并证明了雌激素（E2）和孕激素（Pg）在调节宫颈上皮淋球菌感染中的独特作用。本研究的目的是确定在E2和Pg生理浓度下，类固醇激素受体（SHRs）在原发性宫颈上皮对淋球菌感染的反应中的作用。我们之前的数据表明，淋球菌性宫颈炎的无症状性质可能部分归因于淋球菌破坏补体（C'）替代途径的正常功能，从而通过补体受体3 （CR3）促进侵袭。然而，值得注意的是，类固醇激素（SHs）具有抗炎特性，这在一定程度上归因于其同源细胞受体作为转录因子和/或调节细胞刺激引发的信号级联反应的能力。在这方面，SHRs被证明可以调节一些C'蛋白的表达。该建议的一个独特方面涉及我们使用原代人宫颈上皮细胞（pex）研究妇女淋球菌病的临床相关性。CR3是淋病奈瑟菌在体内和体外利用的主要受体，与宫颈结合并侵入宫颈。虽然CR3存在于顶点细胞上，但它不存在于（人类）男性泌尿生殖道、小鼠雌性生殖道的上皮上，也不存在于永生化/恶性宫颈细胞系上。因此，通过使用顶点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发病机制的某些方面，这些方面是女性感染所特有的，并且被使用其他模型系统所忽视。我们是唯一一个常规使用原代人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，这使得永生化细胞系在阐明SHR功能方面的作用有限。因此，我们非常适合提供SHs对宫颈生物学和淋球菌发病机制的影响的详细分析。公共卫生相关性：本申请的重点是确定类固醇激素对原发性宫颈上皮的影响，从而对无症状淋球菌性宫颈炎的影响。提出的研究是细菌发病机制的一个重要的和未被充分研究的领域，并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.