Complement and hormone receptor modulation during gonococcal cervical infection

淋球菌宫颈感染期间的补体和激素受体调节

基本信息

批准号：
7640370
负责人：
Jennifer L Edwards
金额：
$ 21.6万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640370
关键词：
Adherence Affect Alternative Complement Pathway Anti-Inflammatory Agents Anti-inflammatory Area Attention Biological Models Biology Cell Line Cell model Cells Cervical Cervicitis Cervix Uteri Chronic Chronic Disease Clinical Data Complement Complement Receptor Data Disease Employee Strikes Epithelial Epithelial Cells Epithelium Estrogens Exhibits Female Functional disorder Gender General Population Genital system Genitourinary system Goals Gonorrhea Health Hormonal Hormone Receptor Hormones Human Infection Inflammatory Invaded Investigation Laboratories Macrophage-1 Antigen Male urethral structure Malignant - descriptor Mediating Menstruation Modeling Molecular Mus Nature Neisseria gonorrhoeae Neonatal Pathogenesis Patients Physiological Prevalence Progesterone Property Reproductive Biology Role Signal Transduction Site Specificity Testing Woman base citrate carrier clinically relevant human male improved in vivo insight men public health relevance receptor receptor expression receptor function reproductive response steroid hormone steroid hormone receptor transcription factor

项目摘要

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.

描述（由申请人提供）：妇女容易发生慢性，通常是严重的后果，这是由于宫颈淋病奈瑟氏菌感染而导致的。尽管临床数据表明，女性淋球菌感染有激素成分，但这一研究途径很少受到关注。我们的数据与这一想法一致，并且在调节宫颈上皮菌的淋球菌感染中表现出不同的作用（E2）和孕酮（PG）。该提议的目的是定义类固醇激素受体（SHR）在E2和PG生理浓度下对原发性宫颈上皮症对淋球可感染的反应的作用。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归因于淋球菌以通过补体受体3（CR3）促进替代补体途径（C'）的替代途径（C'）的正常功能的能力。然而，值得注意的是，类固醇激素（SHS）发挥抗炎特性，部分归因于其同源细胞受体的能力，可作为转录因子和/或调节由细胞刺激触发的信号传导级联。在这方面，SHR被证明可以调节某些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。 CR3是由体内和Ex Vivo促淋病的主要受体，与子宫颈相连并侵入子宫颈。尽管CR3存在于PEX细胞上，但它不存在于（人）泌尿生殖道的上皮，小鼠雌性生殖道，也不是永生/恶性宫颈细胞系。因此，通过将PEX细胞用作较低女性生殖道的模型，我们能够揭示淋病链球菌发病机理的各个方面，这些发病机理特异于女性感染，并且使用其他模型系统已经过度看待。我们是唯一使用原发性人类上皮细胞研究淋球菌发病机理的实验室。此外，最近的数据表明，在永生/恶性宫颈上皮中，SHR表达不存在或严重下调，这使得在SHR功能的阐明中有限效用有限的效用。因此，我们非常适合对SHS对宫颈生物学和淋球菌发病机理的影响进行详细分析。公共卫生相关性：该应用的重点是定义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宫颈炎产生影响。拟议的研究是细菌发病机理的重要且不足的区域，直接适用于人类健康。