Modulation of the host response to influenza virus infection: The IKKe Kinase Project Summary Influenza viruses circulate in both avian and human hosts and account for annual outbreaks resulting in significant morbidity, mortality and the constant threat of a worldwide pandemic. The viruses'evolutionary success is largely credited to its capacity for evading host immunity. Viral pathogenicity itself is thought to result from the robust cellular response to infection that is rendered ineffective by the expression of virus- specific antagonistic proteins. Therefore, the success of future antiviral drug and vaccine design demands a thorough understanding of these host-pathogen interactions. Recently, an IKK-related kinase called IKKe was identified as a novel molecular determinant in the cellular response to influenza virus. Mice lacking this kinase were unable to inhibit virus replication and were thus rendered hypersusceptible to infection. These data suggest that this kinase, and the cellular pathway which it controls, serve as exciting new candidate antiviral targets. This proposal focuses on three interrelated aims to better characterize the role of IKKe and influenza virus-induced pathogenicity. The focus of Aim 1 is to identify the kinase responsible for IKKe activation following influenza-induced cytokine signaling.
Aim 2 is to elucidate the function of IKKe-mediated phosphorylation of STAT1.
Aim 3 is to characterize how the levels of IKKe modulate the cellular transcriptome following influenza virus infection. This proposal is thus designed to further elucidate the cellular response to influenza virus infection, to identify determinants of viral pathogenicity, and to discover novel components for use in antiviral drug and vaccine design.

Public Health Relevance

Modulation of the host response to influenza virus infection: The IKK? Kinase Project Narrative Given the ever-present global burden of influenza virus, the study of host-virus interactions can result in discoveries that have immediate impact on human health. We have discovered that IKK?, a virus- and interferon-activated kinase, induces a cellular response that is critical in controlling influenza virus replication. This application focuses on understanding IKK?-mediated anti-viral signaling in order to identify novel targets for immune modulation and the treatment of influenza virus pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080624-04
Application #
8282658
Study Section
Virology - B Study Section (VIRB)
Program Officer
Hauguel, Teresa M
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$407,661
Indirect Cost
$162,636
Name
Icahn School of Medicine at Mount Sinai
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Rajsbaum, Ricardo; Versteeg, Gijs A; Schmid, Sonja et al. (2014) Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKK? kinase-mediated antiviral response. Immunity 40:880-95
Chua, Mark A; Schmid, Sonja; Perez, Jasmine T et al. (2013) Influenza A virus utilizes suboptimal splicing to coordinate the timing of infection. Cell Rep 3:23-9
Ng, Sze-Ling; Friedman, Brad A; Schmid, Sonja et al. (2011) IýýB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses. Proc Natl Acad Sci U S A 108:21170-5