West Nile Virus (WNV) is a NIAID category B mosquito-borne flavivirus that causes fatal outbreaks of epidemic encephalitis in Europe, Asia, the Middle East, and North America, including the United States. Using genetically deficient mice, we have recently demonstrated that a deficiency of the complement components C1q or C4 leads to a disseminated, fatal WNV infection. Based on these observations, the proposed research plans to directly determine how activation of the classical and lectin complement pathways inhibits WNV infection. These results may be directly applicable to other related NIAID Category A and B flavivirus human pathogens.
In Specific Aim 1, we will define the protective anti-WNV function of the lectin pathway of complement activation using mannan-binding lectin serine peptidase 2 (MASP-2)-/- and mannose binding lectin (MBL)-/- mice.
In Specific Aim 2, the role and mechanism of C1q modulation of antibody neutralization will be examined. This information will be directly applied to generating novel recombinant antibody therapeutic reagents with increased complement-dependent effector functions.
In Specific Aim 3, the mechanisms by which complement primes the amplitude and specificity of memory B cell responses against WNV will be studied. The identification of specific pathways for controlling early dissemination of WNV and for triggering long-term immune protection will enhance our understanding of WNV pathogenesis and provide novel strategies for prophylaxis and/or therapeutic intervention.
Given the lack of existing therapies or vaccines against WNV and other globally important flaviviruses, and the increasing number of human cases, it is critical to elucidate mechanisms by which the innate immune response limits infection and disease. The experiments outlined in this grant may provide new avenues for optimizing antibody therapeutics and novel strategies for vaccines or adjuvants to induce focused and protective antibody response of long-term duration.
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