West Nile virus (WNV) is an NIAID Category B infectious zoonotic agent that causes severe neurological disease in humans and other animals. The virus and host processes that control WNV infection and immunity are not fully understood. Our preliminary studies indicate that susceptibility to WNV infection is in part regulated by innate immune defenses triggered by pathogen-associated molecular pattern (PAMP) recognition of WNV RNA by the RIG-I-like receptors (RLRs), RIG-I and MDA5. These defenses are mediated by the type I interferon (IFN) antiviral response that includes a novel IKK? signaling pathway of STAT1-serine 708 phosphorylation and the actions of specific antiviral effector interferon-stimulated genes (ISGs). Our preliminary studies also have revealed that pathogenic WNV disrupts IKK? signaling to attenuate IFN actions and evade antiviral immunity. These observations identify STAT1 serine-708 phosphorylation control as a virulence determinant of WNV infection. The proposed studies will investigate the hypothesis that WNV infection outcome is regulated by virus/host interactions that modulate RLR signaling and specific IFN-? innate immune defenses in distinct cell types. Our studies will include Aims to: (1) Define the dual role of RIG-I and MDA5 in restricting WNV infection [and modulating adaptive immunity], (2) Identify the PAMPs within the WNV RNA that are recognized by RIG-I and MDA5, (3) Define the IFN-?-mediated antiviral pathways that specifically restrict WNV infection in neurons, which are key targets of in vivo infection, and (4) Determine the mechanism of immune escape from the IKK??pathway.

Public Health Relevance

Public Health Statement: West Nile virus (WNV), an important member of the Flavivirus genus, is now the leading cause of epidemic encephalitis in the United States, and continues to spread globally. Our experiments will assess the virus and host interface that regulates the innate immune response and controls WNV pathogenesis, and will reveal novel targets for therapeutic development to suppress flavivirus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104002-01A1
Application #
8565626
Study Section
Special Emphasis Panel (ZRG1-IDM-B (02))
Program Officer
Repik, Patricia M
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$713,273
Indirect Cost
$176,342
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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