Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses
Vineet D. Menachery,
Amie J. Eisfeld,
Alexandra Schäfer,
Laurence Josset,
Amy C. Sims,
Sean Proll,
Shufang Fan,
Chengjun Li,
Gabriele Neumann,
Susan C. Tilton,
Jean Chang,
Lisa E. Gralinski,
Casey Long,
Richard Green,
Christopher M. Williams,
Jeffrey Weiss,
Melissa M. Matzke,
Bobbie-Jo Webb-Robertson,
Athena A. Schepmoes,
Anil K. Shukla,
Thomas O. Metz,
Richard D. Smith,
Katrina M. Waters,
Michael G. Katze,
Yoshihiro Kawaoka,
Ralph S. Baric
Affiliations
Vineet D. Menachery
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Amie J. Eisfeld
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
Alexandra Schäfer
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Laurence Josset
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Amy C. Sims
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Sean Proll
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Shufang Fan
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
Chengjun Li
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
Gabriele Neumann
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
Susan C. Tilton
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Jean Chang
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Lisa E. Gralinski
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Casey Long
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Richard Green
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Christopher M. Williams
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Jeffrey Weiss
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Melissa M. Matzke
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Bobbie-Jo Webb-Robertson
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Athena A. Schepmoes
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Anil K. Shukla
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Thomas O. Metz
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Richard D. Smith
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Katrina M. Waters
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Michael G. Katze
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
Yoshihiro Kawaoka
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
Ralph S. Baric
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
ABSTRACT The broad range and diversity of interferon-stimulated genes (ISGs) function to induce an antiviral state within the host, impeding viral pathogenesis. While successful respiratory viruses overcome individual ISG effectors, analysis of the global ISG response and subsequent viral antagonism has yet to be examined. Employing models of the human airway, transcriptomics and proteomics datasets were used to compare ISG response patterns following highly pathogenic H5N1 avian influenza (HPAI) A virus, 2009 pandemic H1N1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome CoV (MERS-CoV) infection. The results illustrated distinct approaches utilized by each virus to antagonize the global ISG response. In addition, the data revealed that highly virulent HPAI virus and MERS-CoV induce repressive histone modifications, which downregulate expression of ISG subsets. Notably, influenza A virus NS1 appears to play a central role in this histone-mediated downregulation in highly pathogenic influenza strains. Together, the work demonstrates the existence of unique and common viral strategies for controlling the global ISG response and provides a novel avenue for viral antagonism via altered histone modifications. IMPORTANCE This work combines systems biology and experimental validation to identify and confirm strategies used by viruses to control the immune response. Using a novel screening approach, specific comparison between highly pathogenic influenza viruses and coronaviruses revealed similarities and differences in strategies to control the interferon and innate immune response. These findings were subsequently confirmed and explored, revealing both a common pathway of antagonism via type I interferon (IFN) delay as well as a novel avenue for control by altered histone modification. Together, the data highlight how comparative systems biology analysis can be combined with experimental validation to derive novel insights into viral pathogenesis.
