Role of C7 in Resistance to Neisseria Infections

描述（由申请人提供）：补体系统在对细菌感染的先天免疫反应中起关键作用。无论经典途径、替代途径还是凝集素途径启动补体激活，补体系统最终都会产生膜攻击复合物（MAC）。由C5b、C6、C7、C8和C9 （C5b-9）组成的MAC不仅具有直接的溶菌活性，而且通过可溶性C5b-9和亚溶MAC沉积在宿主有核细胞上调节细胞免疫应答。缺乏C6、C7和C8而不缺乏C9的个体感染淋病奈瑟菌和脑膜炎奈瑟菌的风险更高。虽然这些人的感染风险非常高，但矛盾的是，死亡风险远低于一般人群。虽然有人推测这是由于缺乏MAC依赖的细菌细胞壁成分释放和炎症反应的衰减，但几乎没有直接证据支持这一观点。此外，由于缺乏缺乏末端补体成分的动物模型，我们对C5b-9复合物与宿主免疫反应相互作用的复杂性的理解受到限制。目前的建议旨在确定C5b-9增强宿主抵抗奈瑟菌感染的能力的机制，在C7靶向缺乏的新生小鼠中。利用已建立的播散性淋病奈瑟菌感染模型，将在细胞和分子水平上研究C7缺陷小鼠，从而无法形成膜攻击复合物，以确定对细菌清除和杀死至关重要的C5b-9依赖途径。这些途径将在体内得到验证。这种新型模型系统的使用不仅可以增强我们对C5b-9在宿主防御奈瑟菌感染中的作用的理解，还可以增强我们对C5b-9调节免疫过程的机制的理解。

DESCRIPTION (provided by applicant): The complement system plays a critical role in the innate immune response to bacterial infection. Regardless whether the classical, the alternative, or the lectin pathway initiates complement activation, the complement system ultimately generates the membrane attack complex (MAC). The MAC, composed of C5b, C6, C7, C8, and C9 (C5b-9), not only has direct bacteriolytic activity but also modulates cellular immune response via soluble C5b-9 and sub- lytic MAC deposition on host nucleated cells. Individuals with deficiencies of C6, C7, and C8, but not C9 are at a uniquely higher risk for infection with Neisseria gonorrhoeae and Neisseria meningitidis. While there is a much high risk of infection in these individuals, paradoxically the risk of mortality is much lower than the general population. While is has been speculated that this is due to a lack of MAC dependent release of bacterial cell wall components and attenuation of inflammatory responses, there is little direct evidence to support this. Furthermore our understanding of the complexities of the interactions of the C5b-9 complex with the host immune response has been limited by a lack of animal models deficient in terminal complement components. The current proposal seeks to define the mechanisms by which C5b-9 enhances the ability of the host to resist Neisseria infections in a newly generated mouse with a targeted deficiency in C7. Using an established model of disseminated Neisseria gonorrhoeae infection, mice deficient in C7, and thus unable to form the membrane attack complex, will be investigated at the cellular and molecular levels in order to identify C5b-9 dependent pathways critical to the clearance and killing of the bacteria. These pathways will then be validated in vivo. The use of this novel model system should enhance not only our understanding of the role of C5b-9 in host defense against Neisseria infection but also our understanding of the mechanisms by which C5b-9 modulates immunologic processes in general. PUBLIC HEALTH RELEVANCE: This proposal seeks to define the mechanisms by which the membrane attack complex (MAC) of complement enhances the ability of the host to resist Neisseria infections. Using a newly developed C7 deficient mouse, we will identify and characterize MAC dependent cellular and molecular pathways critical to protection from Neisseria gonorrhoeae, and validate these findings in a whole animal model of Neisseria infection.