Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS.
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.
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Line S
LS
Reinert
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Department of Molecular Pathogenesis of Viruses, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
Katarína
K
Lopušná
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Henriette
H
Winther
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Chenglong
C
Sun
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Martin K
MK
Thomsen
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Ramya
R
Nandakumar
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.|Department of Infectious Diseases, Aarhus University Hospital Skejby, 8200 Aarhus N, Denmark.
Trine H
TH
Mogensen
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark.
Morten
M
Meyer
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.
Christian
C
Vægter
Department of Clinical Medicine, University of Aarhus, 8200 Aarhus N, Denmark.
Jens R
JR
Nyengaard
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Katherine A
KA
Fitzgerald
Department of Biomedicine, University of Aarhus, Bartholins Allé 6, 8000 Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, 8000 Aarhus C, Denmark.
Søren R
SR
Paludan
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D020803:Encephalitis, Herpes Simplex / Q000188:drug therapy / Q000235:genetics / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D009713:Nucleotidyltransferases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D000998:Antiviral Agents; D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase