Modulation of the host response to influenza virus infection: The IKKe Kinase

Summary

Principal Investigator: Benjamin R tenOever
Abstract: 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.
Funding Period: 2009-06-15 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Transcription factor redundancy ensures induction of the antiviral state
    Sonja Schmid
    Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Biol Chem 285:42013-22. 2010
  2. pmc IκB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses
    Sze Ling Ng
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 108:21170-5. 2011
  3. pmc Influenza A virus utilizes suboptimal splicing to coordinate the timing of infection
    Mark A Chua
    Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cell Rep 3:23-9. 2013
  4. pmc Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response
    Ricardo Rajsbaum
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA
    Immunity 40:880-95. 2014

Detail Information

Publications4

  1. pmc Transcription factor redundancy ensures induction of the antiviral state
    Sonja Schmid
    Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Biol Chem 285:42013-22. 2010
    ....
  2. pmc IκB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses
    Sze Ling Ng
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 108:21170-5. 2011
    ..We conclude that IKKε plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways...
  3. pmc Influenza A virus utilizes suboptimal splicing to coordinate the timing of infection
    Mark A Chua
    Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cell Rep 3:23-9. 2013
    ..Together, these data demonstrate that coordination of the influenza A virus life cycle is set by a "molecular timer" that operates on the inefficient splicing of a virus transcript...
  4. pmc Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response
    Ricardo Rajsbaum
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA
    Immunity 40:880-95. 2014
    ..Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response. ..

Research Grants31

  1. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  2. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  3. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  4. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  5. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  6. MECHANISMS OF BREAST DEVELOPMENT AND CARCINOGENESIS
    Robert A Weinberg; Fiscal Year: 2013
    ..abstract_text> ..
  7. Cellular Immunity to Category A-C Viruses in Humans
    ROBERT WILLIAM FINBERG; Fiscal Year: 2013
    ....
  8. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  9. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  10. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  11. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..
  12. Protein homeostasis mechanisms underlying enterovirus replication and evolution
    Raul Andino; Fiscal Year: 2013
    ..Core A: Administrative Core;and Core B: "High-throughput functional genomics and proteomics core. ..