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

• 批准号: 7849963
• 负责人: Jennifer L Edwards
• 金额: $ 18万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849963
• 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

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）：女性很容易因宫颈感染淋病奈瑟菌而产生慢性且通常严重的后果。尽管临床数据表明女性淋球菌感染与激素成分有关，但这一研究途径很少受到关注。我们的数据与这一观点一致，并证明雌激素（E2）和孕激素（Pg）在调节宫颈上皮淋球菌感染中的不同作用。本提案的目的是确定类固醇激素受体 (SHR) 在 E2 和 Pg 生理浓度下原代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，淋菌性宫颈炎的无症状性质可能部分归因于淋菌能够破坏补体替代途径（C'）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（SH）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发挥作用和/或调节细胞刺激触发的信号级联的能力。在这方面，SHR 显示​​可调节某些 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 是淋病奈瑟菌在体内和体外利用的主要受体，用于与子宫颈结合并侵入子宫颈。尽管 CR3 存在于 pex 细胞上，但它不存在于（人）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，我们已经能够揭示女性感染特有的淋病奈瑟菌发病机制的各个方面，而这些方面已被其他模型系统的使用所忽视。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，永生化/恶性宫颈上皮细胞中 SHR 表达缺失或严重下调，使得永生细胞系在阐明 SHR 功能方面的效用有限。因此，我们非常适合详细分析 SH 对宫颈生物学和淋球菌发病机制的影响。公共健康相关性：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，从而确定对无症状淋菌性宫颈炎的影响。拟议的研究是细菌发病机制的一个重要且尚未得到充分研究的领域，可直接应用于人类健康。