Gonococcal Inflammatory Immune Responses

描述（由申请人提供）：本探索性R21申请将研究新描述的“Th17免疫轴”在阴道淋球菌感染小鼠模型中的意义。目的是确定淋病奈瑟菌是否可以诱导Th17细胞的发育，并验证通过白细胞介素(IL)-17受体的信号传导在引发先天免疫反应中很重要的假设。产生IL-17的Th17细胞已被证明在先天免疫/炎症反应中发挥重要作用，并在粘膜感染反应中引起中性粒细胞内流。淋病奈瑟菌是淋病的病原体，通常会诱导中性粒细胞流入感染部位，在生殖器分泌物中存在与中性粒细胞相关的淋球菌是典型的诊断标准。像其他病原体一样，淋病奈瑟菌与宿主组织相互作用，引发有利于其生存的反应，并且自然感染不会诱导对重复感染的保护性免疫。因此，有人认为淋病奈瑟菌积极干扰适应性免疫反应的发展，并推测Th17细胞的激发有助于这一点。具体目的是：(1)评价淋病奈瑟菌在体外、体内小鼠细胞和体外人血单核细胞中诱导Th17细胞发育和关键细胞因子产生的能力；(2)比较正常野生型小鼠和IL-17受体缺陷小鼠对淋病奈瑟菌阴道攻击的反应，以确定通过该受体的信号传导是否在中性粒细胞募集和转移适应性免疫反应中起关键作用。阐明这一宿主对淋病奈瑟菌反应的新途径将大大提高对淋病感染免疫致病机制的理解，并促进对淋病的新干预措施的开发，这是一个明显的需要。公共卫生相关性：淋病是美国第二常见的法定传染病，疾病预防控制中心报告近年来有超过30万例，尽管真实发病率据信是该数字的两倍；据估计，全世界每年有超过6000万的新感染病例。妇女首当其冲受到感染，这可能导致严重的生殖健康问题，包括盆腔炎、不孕症和异位妊娠的风险。众所周知，淋病对反复感染不会产生免疫力，但目前还没有控制淋病的疫苗，抗生素耐药性正在蔓延。这一建议将应用免疫学领域的重要新发现来确定免疫系统与淋球菌相互作用的方式，这是一个目前知之甚少的领域。

DESCRIPTION (provided by applicant): This exploratory R21 application will investigate the significance of the newly described "Th17 axis of immunity" in a mouse model of vaginal gonococcal infection. The objectives are to determine whether Neisseria gonorrhoeae can induce the development of Th17 cells and to test the hypothesis that signaling through the interleukin (IL)-17 receptor is important in the elicitation of the innate immune response. Th17 cells, which produce IL-17, have been shown to play a major role in innate immune/inflammatory responses and in the elicitation of the neutrophil influx in response to mucosal infections. N. gonorrhoeae, the agent of gonorrhea, typically induces a neutrophil influx into the site of infection and the presence in genital secretions of gonococci associated with neutrophils is a classic diagnostic criterion. Like other pathogens, N. gonorrhoeae interacts with host tissues to elicit responses that favor its survival, and the natural infection does not induce protective immunity against repeated infection. It has therefore been suggested that N. gonorrhoeae actively interferes with the development of adaptive immune responses, and it is hypothesized that the elicitation of Th17 cells contributes to this. The Specific Aims are: (1) To evaluate the ability of N. gonorrhoeae to induce the development of Th17 cells and the production of key cytokines in mouse cells in vitro and in vivo, and in human blood mononuclear cells in vitro; (2) To compare the responses of normal wild- type and IL-17 receptor-deficient mice to vaginal challenge with N. gonorrhoeae in order to determine whether signalling through this receptor is critical in the recruitment of neutrophils and in deflecting adaptive immune responses. Elucidation of this novel pathway of the host response to N. gonorrhoeae will greatly improve comprehension of the immuno-pathogenic mechanisms of gonococcal infection and facilitate the development of new interventions against gonorrhea, for which there is a demonstrable need. PUBLIC HEALTH RELEVANCE: Gonorrhea is the second-most-frequent, notifiable infectious disease in the United States and the CDC reports over 300,000 cases in recent years [59], although the true incidence is believed to be double that figure; world- wide incidence is estimated to be over 60 million new infections per year [60]. Women bear the brunt of the infection which can lead to serious reproductive health problems including pelvic inflammatory disease, infertility, and risk for ectopic pregnancy, and while it is well known that gonorrhea does not generate immunity to repeated infection, no vaccines exist to control it and antibiotic resistance is spreading. This proposal will apply important new findings from the field of immunology to determine the way in which the immune system interacts with the gonococcus bacterium, an area that is poorly understood at present.