This proposal is to characterize the role of interleukin 22 (IL-22), a member of the IL-10-related cytokine family, in the pathogenesis of West Nile encephalitis using a mouse model. IL-22 has been implicated in both chronic inflammatory diseases and infectious diseases. On one hand, IL-22 contributes to pathogenesis of psoriasis and multiple sclerosis. On the other hand, IL-22 protects the liver from immune system-mediated damage during hepatitis, helps maintain epithelial barriers and induces secretion of anti-microbial peptides by the epithelia in response to extracellular pathogen infection, such as K. pneumoniae. However, to our best knowledge, the in vivo role of IL-22 in viral infections remains largely elusive. West Nile virus (WNV) is a neurotropic ssRNA flavivirus that has caused over 1000 deaths in the United States since 1999. However, no human vaccines or specific therapeutics are available. Interestingly we have recently shown that IL-22 does not influence the innate immune response and WNV propagation in the peripheral system, but facilitates the pathogenesis of West Nile encephalitis. We hereby propose to test the prophylactic/therapeutic potential of IL-22 antagonists and hypothesize that IL-22 promotes WNV entry into the central nervous system. Specifically we will 1) test the prophylactic/therapeutic potential of IL-22 soluble receptor IL- 22BP and neutralizing antibodies, and 2) Investigate the mechanism by which IL-22 contributes to WNV pathogenesis. If successful, these studies may lead to new strategies for the prevention of West Nile virus infection. This paradigm would also be applicable to other neuroinvasive viral pathogens of medical importance like Japanese encephalitis and Saint Louis encephalitis virus.

Public Health Relevance

West Nile virus has caused over 1000 deaths since 1999 in the United States. However, no specific therapeutics or human vaccines are available. This project is to test the prophylactic/therapeutic potential of interleukin-22 antagonists and investigate how IL-22 influences West Nile virus pathogenesis using a mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI099625-02
Application #
8601165
Study Section
Virology - B Study Section (VIRB)
Program Officer
Repik, Patricia M
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$83,250
Indirect Cost
$33,250
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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