Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS
Line S. Reinert, Katarína Lopušná, Henriette Winther, Chenglong Sun, Martin K. Thomsen, Ramya Nandakumar, Trine H. Mogensen, Morten Meyer, Christian Vægter, Jens R. Nyengaard, Katherine A. Fitzgerald & Søren R. Paludan
Nature Communications 7, Article number: 13348 (2016)
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Glial biology Infectious diseases Interferons Viral host response
Received: 06 November 2015 Accepted: 22 September 2016 Published online: 10 November 2016
Figure 1: Mice deficient in cGAS or STING are susceptible to HSE and exhibit impaired antiviral responses.
Abstract
Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS–STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS–STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.
Acknowledgements
The technical assistance of Kirsten Stadel Petersen is greatly appreciated. We also thank the AU FACS Core facility for technical help. We thank David A. Leib for teaching the ocular HSV-1 infection model. This work was funded by The Danish Medical Research Council (12-124330), The Novo Nordisk Foundation, The Lundbeck Foundation (grant no. R34-3855), Aarhus University Research Foundation (all S.R.P.), The EU FP7 Mobilex programme (grant number 1333-00090A; M.K.T.) and The Chinese Scholarship Council (C.S.).
Author information
Affiliations
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark
Line S. Reinert, Katarína Lopušná, Henriette Winther, Chenglong Sun, Martin K. Thomsen, Ramya Nandakumar, Trine H. Mogensen, Christian Vægter & Søren R. Paludan
Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark
Line S. Reinert, Henriette Winther, Chenglong Sun, Martin K. Thomsen, Ramya Nandakumar, Trine H. Mogensen & Søren R. Paludan
Department of Molecular Pathogenesis of Viruses, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic
Katarína Lopušná
Department of Infectious Diseases, Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark
Trine H. Mogensen
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark
Morten Meyer
Department of Clinical Medicine, University of Aarhus, 8200 Aarhus N, Denmark
Jens R. Nyengaard
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
Katherine A. Fitzgerald
Contributions
L.S.R. and S.R.P. conceived of the study. L.S.R., K.L., H.W., C.S., M.K.T. and R.N. performed experiments. L.S.R., K.L. and H.W. analysed data. T.H.M., M.M., C.V., J.R.N. and K.A.F. provided reagents and intellectual guidance. All authors were involved in the discussion of results. L.S.R. and S.R.P. wrote the manuscript, and all authors commented on the manuscript.
Competing interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to Søren R. Paludan.
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