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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057160-10
Application #
8446485
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$289,466
Indirect Cost
$74,136
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr et al. (2016) Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies. Proc Natl Acad Sci U S A 113:E3609-18
Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180
Miao, Chunhui; Li, Minghua; Zheng, Yi-Min et al. (2016) Cell-cell contact promotes Ebola virus GP-mediated infection. Virology 488:202-15
Zhao, Jincun; Vijay, Rahul; Zhao, Jingxian et al. (2016) MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis. J Virol 90:7098-108
Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69
Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373
Grinnage-Pulley, Tara; Mu, Yang; Dai, Lei et al. (2016) Dual Repression of the Multidrug Efflux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. Front Microbiol 7:1097
Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proc Natl Acad Sci U S A 113:1351-6
Grinnage-Pulley, Tara; Zhang, Qijing (2015) Genetic Basis and Functional Consequences of Differential Expression of the CmeABC Efflux Pump in Campylobacter jejuni Isolates. PLoS One 10:e0131534
Nukui, Masatoshi; Mori, Yasuko; Murphy, Eain A (2015) A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. J Virol 89:2615-27

Showing the most recent 10 out of 325 publications