Role of C7 in Resistance to Neisseria Infections

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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.