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

• Published in: Nature microbiology Vol. 4; no. 7; pp. 1096 - 1104
• Main Authors: Yamane, Daisuke, Feng, Hui, Rivera-Serrano, Efraín E., Selitsky, Sara R., Hirai-Yuki, Asuka, Das, Anshuman, McKnight, Kevin L., Misumi, Ichiro, Hensley, Lucinda, Lovell, William, González-López, Olga, Suzuki, Ryosuke, Matsuda, Mami, Nakanishi, Hiroki, Ohto-Nakanishi, Takayo, Hishiki, Takayuki, Wauthier, Eliane, Oikawa, Tsunekazu, Morita, Kouichi, Reid, Lola M., Sethupathy, Praveen, Kohara, Michinori, Whitmire, Jason K., Lemon, Stanley M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2019; Nature Publishing Group
• Subjects: 13/89; 13/95; 38/91; 45/77; 631/250/262; 631/326/596/2553; Animals; Biomedical and Life Sciences; Cell culture; Cell Nucleus - metabolism; Cells, Cultured; Dengue fever; Feces - virology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Knockout Techniques; Hepatitis A; Hepatocytes; Hepatocytes - immunology; Hepatocytes - metabolism; Hepatocytes - virology; Humans; Immunity, Innate - genetics; Infectious Diseases; Interferon; Interferon regulatory factor; Interferon regulatory factor 1; Interferon regulatory factor 3; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Kinetics; Letter; Life Sciences; Liver - virology; Medical Microbiology; Mice; Microbiology; Mitochondria; Parasitology; RNA viruses; RNA Viruses - physiology; RNA, Small Interfering; Signal transduction; Signal Transduction - genetics; Stat1 protein; Toll-like receptors; Transcription factors; Virology; Virus Replication; Viruses
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-019-0425-6

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 interferons 1 . RNA viruses have evolved sophisticated strategies to disrupt these signalling pathways and evade elimination by cells, attesting to their importance 2 . 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. Using a short-hairpin RNA-based depletion strategy coupled with high throughput RNA sequencing, the authors unravel a layer of intrinsic immunity to positive-strand RNA viruses in immortalized hepatocytes that relies on basal expression levels of interferon regulatory factor 1 maintaining the transcription of a suite of antiviral genes.