The roles of the anaphylatoxin receptors during invasive disease as well as mucosal colonization caused by Neisseria meningitidis

过敏毒素受体在脑膜炎奈瑟菌引起的侵袭性疾病和粘膜定植过程中的作用

• 批准号: 278593213
• 负责人: Dr. Kay Ole Johswich
• 金额: --
• 依托单位: Institut für Hygiene und Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/278593213?language=en
• 关键词: roles; anaphylatoxin; receptors; during; invasive

Neisseria meningitidis (meningococcus, Nme) is the causative agent of fulminant sepsis and meningitis which can lead to death within 24 hours. Usually, however, Nme colonizes the nasopharynx without causing disease and is found in approximately 10% of the general population. The complement system represents the most important branch of the innate immune system to control invasive meningococcal disease (IMD). Especially the contribution of the terminal membrane attack complex in defence against Nme is well characterized. Yet, complement activation also liberates the small pro-inflammatory split products C3a and C5a, the so-called anaphylatoxins (AT). These highly potent mediators of inflammation activate a set of three cognate receptors, the anaphylatoxin receptors (ATR) C3aR, C5aR and C5L2, which can exacerbate systemic inflammation. There is a surprising lack of data regarding the contribution of the AT and ATR to IMD pathophysiology or their role during asymptomatic Nme colonization of the respiratory mucosa. In the first part of the project, the influence of the individual ATR will be delineated in an intraperitoneal infection model of meningococcal sepsis by comparing the course of disease in wild-type versus knockout mice lacking ATR. The obtained results will be corroborated by targeting the AT as well as ATR by specific antibodies or peptide antagonists, which will also determine their potential as therapeutic targets in IMD. Specific in vivo depletion protocols as well as in vitro experiments will identify the cells which mediate the ATR-dependent IMD immunopathology. In the second part of the project, the overall role of complement in the mucosal defence against Nme will be characterized. Especially the role of the ATR in the local inflammatory response will be elaborated in this context with respect the recruitment of phagocytes, which clear Nme mucosal colonization. Furthermore, the impact of ATR on the adaptive immune response towards Nme will be elucidated with focus on the generation of protective Nme-specific IgG subclasses, which target complement activation (IgG2a, IgG2b). In order to consider the human-restricted tropism of Nme, these studies will be conducted using a novel transgenic mouse expressing human CEACAM1, which allows for Nme colonization in mice, in conjunction with knockout mice lacking ATR or other complement components. Taken together, this project will, for the first time, define the role of complement-mediated inflammation during infection with Nme. To do so, this project will embrace the dichotomy of both, the Nme lifestyle (commensal during mucosal colonization versus pathogenic during sepsis) as well as the ATR-mediated inflammation (physiologic during mucosal colonization versus deregulated during sepsis). Therefore, this project will bear novel insights for the fields of research on pathogenic Neisseriae as well as on the complement system.

脑膜炎奈瑟菌（脑膜炎球菌，Nme）是暴发性脓毒症和脑膜炎的病原体，可导致24小时内死亡。然而，Nme通常定植于鼻咽而不引起疾病，并且在大约10%的一般人群中发现。补体系统代表了先天免疫系统中控制侵袭性脑膜炎球菌病（IMD）的最重要的分支。特别是末端膜攻击复合物在防御Nme中的贡献得到了很好的表征。然而，补体激活也释放了小的促炎分裂产物C3a和C5a，即所谓的过敏毒素（AT）。这些高度有效的炎症介质激活一组三种同源受体，即过敏毒素受体（ATR）C3aR、C5aR和C5L2，其可加剧全身炎症。令人惊讶的是，缺乏关于AT和ATR对IMD病理生理学的贡献或它们在呼吸道粘膜的无症状Nme定殖期间的作用的数据。在该项目的第一部分中，将通过比较野生型与缺乏ATR的基因敲除小鼠的疾病过程，在脑膜炎球菌败血症的腹膜内感染模型中描绘个体ATR的影响。通过特异性抗体或肽拮抗剂靶向AT以及ATR来证实所获得的结果，这也将确定它们作为IMD治疗靶点的潜力。特定的体内消耗方案以及体外实验将鉴定介导ATR依赖性IMD免疫病理学的细胞。在该项目的第二部分中，将描述补体在粘膜防御Nme中的总体作用。特别是ATR在局部炎症反应中的作用将在这种情况下详细说明吞噬细胞的招募，清除Nme粘膜定植。此外，ATR对针对Nme的适应性免疫应答的影响将被阐明，重点是保护性Nme特异性IgG亚类的产生，其靶向补体激活（IgG2a，IgG2b）。为了考虑Nme的人类限制性向性，将使用表达人CEACAM1的新型转基因小鼠（其允许Nme在小鼠中定殖）与缺乏ATR或其他补体组分的敲除小鼠联合进行这些研究。总之，该项目将首次定义Nme感染期间补体介导的炎症的作用。为此，该项目将包括Nme生活方式（粘膜定植期间的寄生虫与脓毒症期间的致病性）以及ATR介导的炎症（粘膜定植期间的生理性与脓毒症期间的失调）的二分法。因此，该项目将为致病性奈瑟氏球菌以及补体系统的研究领域提供新的见解。