Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner
Aminu S. Jahun,
Frederic Sorgeloos,
Yasmin Chaudhry,
Sabastine E. Arthur,
Myra Hosmillo,
Iliana Georgana,
Rhys Izuagbe,
Ian G. Goodfellow
Affiliations
Aminu S. Jahun
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK; Corresponding author
Frederic Sorgeloos
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK; Université catholique de Louvain, de Duve Institute, MIPA-VIRO 74-49, 74 Avenue Hippocrate, B-1200 Brussels, Belgium
Yasmin Chaudhry
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK
Sabastine E. Arthur
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK
Myra Hosmillo
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK
Iliana Georgana
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK
Rhys Izuagbe
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK
Ian G. Goodfellow
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital Level 5, Hills Road, Cambridge CB2 0QQ, UK; Corresponding author
Summary: The cGAS-STING pathway is central to the interferon response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here, we show that the cGAS-STING pathway also contributes to the interferon response against noroviruses, currently the commonest causes of infectious gastroenteritis worldwide. We show a significant reduction in interferon-β induction and a corresponding increase in viral replication in norovirus-infected cells after deletion of STING, cGAS, or IFI16. Further, we find that immunostimulatory host genome-derived DNA and mitochondrial DNA accumulate in the cytosol of norovirus-infected cells. Lastly, overexpression of the viral NS4 protein is sufficient to drive the accumulation of cytosolic DNA. Together, our data find a role for cGAS, IFI16, and STING in the restriction of noroviruses and show the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus.
