Antiviral activity of bone morphogenetic proteins and activins.

Lucy A Eddowes, Kinda Al-Hourani, Narayan Ramamurthy, Jamie Frankish, Hannah T Baddock, Cynthia Sandor, John D Ryan, Dahlene N Fusco, João Arezes, Eleni Giannoulatou, Sara Boninsegna, Stephane Chevaliez, Benjamin M J Owens, Chia Chi Sun, Paolo Fabris, Maria Teresa Giordani, Diego Martines, Slobodan Vukicevic, John Crowe, Herbert Y Lin, Jan Rehwinkel, Peter J McHugh, Marco Binder, Jodie L Babitt, Raymond T Chung, Matthew W Lawless, Andrew E Armitage, Caleb Webber, Paul Klenerman, Hal Drakesmith

Journal: Nature microbiology 2019;4(2):339-351

PMID: 30510168

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Abstract

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

Address: MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.; Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; Dementia Research Institute, Cardiff University, Cardiff, UK.; Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland.; Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK.; Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.; Department of Surgical Gastroenterological Science, University of Padua, Padova, Italy.; Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK.; Program in Anemia Signaling Research, Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Infectious Diseases and Tropical Medicine, San Bortolo Hospital, Vicenza, Italy.; Department of Surgical Gastroenterological Science, University of Padua, Padova, Italy.; Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Zagreb, Croatia.; Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland.; Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Dublin, Ireland.; Dementia Research Institute, Cardiff University, Cardiff, UK.; Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK.; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.; Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK.; NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. [email protected].; Haematology Theme Oxford Biomedical Research Centre, Oxford, UK. [email protected].

DOI: 10.1038/s41564-018-0301-9

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MeSH Terms: Activins, Antiviral Agents, Bone Morphogenetic Protein 6, Cells, Cultured, Endopeptidases, Gene Expression Regulation, Hepacivirus, Hepatitis C, Hepcidins, Humans, Interferon Regulatory Factors, Interferon-alpha, RNA, Viral, Signal Transduction, Smad1 Protein, Ubiquitin Thiolesterase, Virus Replication, Zika Virus