2. Academic Validation
  3. Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses

Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses

  • Nat Microbiol. 2019 Jul;4(7):1096-1104. doi: 10.1038/s41564-019-0425-6.
Daisuke Yamane 1 2 3 4,  Hui Feng 5 6 7,  Efraín E Rivera-Serrano 5 6 7,  Sara R Selitsky 5,  Asuka Hirai-Yuki 5 6 7 8,  Anshuman Das 5 6 7,  Kevin L McKnight 5 6 7,  Ichiro Misumi 9 10,  Lucinda Hensley 5 6 7,  William Lovell 5 6 7,  Olga González-López 5 6 7,  Ryosuke Suzuki 11,  Mami Matsuda 11,  Hiroki Nakanishi 12,  Takayo Ohto-Nakanishi 13,  Takayuki Hishiki 14,  Eliane Wauthier 5 15,  Tsunekazu Oikawa 5 15 16,  Kouichi Morita 17,  Lola M Reid 5 15,  Praveen Sethupathy 5 18,  Michinori Kohara 14,  Jason K Whitmire 5 9 10,  Stanley M Lemon 19 20 21
Affiliations

Affiliations

  • 1 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. yamane-ds@igakuken.or.jp.
  • 2 Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. yamane-ds@igakuken.or.jp.
  • 3 Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. yamane-ds@igakuken.or.jp.
  • 4 Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan. yamane-ds@igakuken.or.jp.
  • 5 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
  • 6 Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 7 Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8 Division of Experimental Animal Research, National Institute of Infectious Diseases, Tokyo, Japan.
  • 9 Department of Microbiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 10 Department of Immunology and Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 11 Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
  • 12 Research Center for Biosignaling, Akita University,, Akita, Japan.
  • 13 Lipidome Lab Co., Ltd,, Akita, Japan.
  • 14 Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
  • 15 Department of Cell Biology and Physiology Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 16 Division of Gastroenterology and Hepatology, Depertment of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
  • 17 Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
  • 18 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
  • 19 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. smlemon@med.unc.edu.
  • 20 Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. smlemon@med.unc.edu.
  • 21 Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. smlemon@med.unc.edu.
PMID: 30988429 DOI: 10.1038/s41564-019-0425-6
Abstract

Current models of cell-intrinsic immunity to RNA viruses centre on virus-triggered inducible Antiviral responses initiated by RIG-I-like receptors or Toll-like receptors that sense pathogen-associated molecular patterns, and signal downstream through interferon regulatory factors (IRFs), transcription factors that induce synthesis of type I and type III interferons1. RNA viruses have evolved sophisticated strategies to disrupt these signalling pathways and evade elimination by cells, attesting to their importance2. Less attention has been paid to how IRFs maintain basal levels of protection against viruses. Here, we depleted Antiviral factors linked to RIG-I-like Receptor and Toll-like Receptor signalling to map critical host pathways restricting positive-strand RNA virus replication in immortalized hepatocytes and identified an unexpected role for IRF1. We show that constitutively expressed IRF1 acts independently of mitochondrial Antiviral signalling (MAVS) protein, IRF3 and signal transducer and activator of transcription 1 (STAT1)-dependent signalling to provide intrinsic Antiviral protection in actinomycin D-treated cells. IRF1 localizes to the nucleus, where it maintains the basal transcription of a suite of Antiviral genes that protect against multiple pathogenic RNA viruses, including hepatitis A and C viruses, Dengue virus and Zika virus. Our findings reveal an unappreciated layer of hepatocyte-intrinsic immunity to these positive-strand RNA viruses and identify previously unrecognized Antiviral effector genes.

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