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，女性容易发生慢性，通常是严重的后果。虽然临床数据表明，女性淋球菌感染有激素成分，但这种研究途径很少受到关注。我们的数据与这一想法是一致的，并证明了不同的作用，雌激素（E2）和孕激素（Pg）在调制淋球菌感染的宫颈上皮。本提案的目的是确定在生理浓度的E2和Pg下，类固醇激素受体（SHR）在原发性宫颈上皮对淋球菌感染的反应中的作用。我们以前的数据表明，淋球菌宫颈炎的无症状性质可能部分地，这归因于淋球菌能够破坏补体（C '）旁路途径的正常功能，从而通过补体受体3（CR3）。然而，还值得注意的是，类固醇激素（SH）发挥抗炎特性，这部分归因于其同源细胞受体作为转录因子起作用和/或调节由细胞刺激触发的信号级联的能力。在这方面，SHRs被证明可以调节一些C'蛋白的表达。该提案的一个独特方面涉及我们使用原代人宫颈上皮（pex）细胞研究女性淋球菌疾病的临床相关性。CR 3是N.淋病，在体内和离体，与宫颈结合并侵入宫颈。尽管CR 3存在于pex细胞上，但它不存在于（人）雄性泌尿生殖道、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pex细胞作为女性下生殖道的模型，我们已经能够揭示N的各个方面。淋病的发病机制，这是特定的感染妇女和已被忽视的使用其他模型系统。我们是唯一一家常规使用原代人类上皮细胞研究淋球菌发病机制的实验室。此外，最近的数据表明，SHR的表达是不存在的或严重下调永生化/恶性宫颈上皮细胞，使永生细胞系的有限的效用，在阐明SHR的功能。因此，我们是唯一适合提供一个详细的分析，对宫颈生物学和淋球菌发病机制的影响。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细胞的作用，从而确定对无症状淋球菌性宫颈炎的作用。拟议的研究是细菌发病机制的一个重要但尚未充分研究的领域，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.