Role of C7 in Resistance to Neisseria Infections

C7 在抵抗奈瑟菌感染中的作用

• 批准号: 8134950
• 负责人: MICHAEL C BRAUN
• 金额: $ 24.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134950
• 关键词: Animal Model; Apoptotic; Bacteria; Bacterial Infections; Biological Models; Cell Wall; Cells; Chemotaxis; Complement; Complement 3; Complement Activation; Complement Membrane Attack Complex; Complement component C6; Complex; Critical Pathways; Deposition; General Population; Goals; Host Defense; Immune response; Immunologics; In Vitro; Individual; Infection; Inflammation Mediators; Inflammatory Response; Lectin; Lytic; Modeling; Molecular; Morbidity - disease rate; Mus; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Pathway interactions; Play; Predisposition; Process; Production; Reporting; Resistance; Risk; Role; Signal Pathway; Signal Transduction; attenuation; complement C5b; complement system; cytokine; high risk; human disease; in vivo; killings; mortality; mouse model; novel; public health relevance; response; soluble complement C5b-9

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.

描述（由申请人提供）：补体系统在对细菌感染的先天免疫应答中起关键作用。无论是经典途径、旁路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C5 b、C6、C7、C8和C9（C5 b-9）组成的MAC不仅具有直接的溶菌活性，而且通过可溶性C5 b-9和亚溶解MAC沉积在宿主有核细胞上来调节细胞免疫应答。C6、C7和C8缺乏而非C9缺乏的个体感染淋病奈瑟菌和脑膜炎奈瑟菌的风险更高。虽然这些人感染的风险很高，但矛盾的是，死亡风险远低于一般人群。虽然已经推测这是由于细菌细胞壁组分的MAC依赖性释放的缺乏和炎症反应的减弱，但几乎没有直接证据支持这一点。此外，我们的理解的C5 b-9复合物与宿主免疫应答的相互作用的复杂性已受到限制，缺乏动物模型缺乏终末补体成分。目前的建议旨在确定C5 b-9增强宿主抵抗C7靶向缺陷的新产生小鼠中奈瑟氏菌感染的能力的机制。使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研究C7缺陷小鼠，从而无法形成膜攻击复合物，以鉴定对细菌清除和杀灭至关重要的C5 b-9依赖性途径。然后将在体内验证这些途径。使用这种新的模型系统，不仅应该提高我们的理解C5 b-9在宿主防御奈瑟氏菌感染的作用，而且我们的理解的机制，C5 b-9调节免疫过程一般。 公共卫生相关性：该建议旨在确定补体的膜攻击复合物（MAC）增强宿主抵抗奈瑟菌感染的能力的机制。使用新开发的C7缺陷小鼠，我们将确定和表征MAC依赖的细胞和分子途径的关键保护淋病奈瑟菌，并验证这些发现在整个动物模型的奈瑟菌感染。