Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses.
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.


OBJECTIVE
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.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Vineet D
VD
Menachery
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Amie J
AJ
Eisfeld
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Alexandra
A
Schäfer
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Laurence
L
Josset
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Amy C
AC
Sims
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Sean
S
Proll
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Shufang
S
Fan
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Chengjun
C
Li
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Gabriele
G
Neumann
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Susan C
SC
Tilton
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Jean
J
Chang
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lisa E
LE
Gralinski
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Casey
C
Long
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Richard
R
Green
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Christopher M
CM
Williams
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Jeffrey
J
Weiss
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Melissa M
MM
Matzke
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Bobbie-Jo
BJ
Webb-Robertson
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Athena A
AA
Schepmoes
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Anil K
AK
Shukla
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Thomas O
TO
Metz
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Richard D
RD
Smith
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
Katrina M
KM
Waters
Michael G
MG
Katze
Yoshihiro
Y
Kawaoka
Rbaric@email.unc.edu.
Ralph S
RS
Baric
D000818:Animals; D002460:Cell Line; D016000:Cluster Analysis; D017934:Coronavirus / Q000502:physiology*; D018352:Coronavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000502:physiology; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D007370:Interferon Type I; D007372:Interferons / Q000378:metabolism* / Q000494:pharmacology; D065207:Middle East Respiratory Syndrome Coronavirus / Q000502:physiology; D008954:Models, Biological; D011485:Protein Binding; D040901:Proteomics; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism
D006657:Histones; C085820:INS1 protein, influenza virus; D007370:Interferon Type I; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D007372:Interferons