Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Line S Reinert
  • Ahmad S Rashidi, Department of Viroscience, Erasmus Medical Centre, Rotterdam, Rotterdam Cancer Institute (Daniel Den Hoed Kliniek and University Hospital Rotterdam), Rotterdam
  • ,
  • Diana N Tran, Department of Viroscience
  • ,
  • Georgios Katzilieris-Petras
  • ,
  • Astrid K Hvidt, Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark; Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark.
  • ,
  • Mette Gohr, Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark; Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark.
  • ,
  • Stefanie Fruhwürth, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Health and Caring Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden.
  • ,
  • Chiranjeevi Bodda, Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark; Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark.
  • ,
  • Martin K Thomsen
  • Mikkel H Vendelbo
  • Ahmad R Khan, NIHR Biomedical Research Centre, SGPGI Campus, University of Lucknow
  • ,
  • Brian Hansen
  • Petra Bergström, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Health and Caring Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden.
  • ,
  • Lotta Agholme, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Health and Caring Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden.
  • ,
  • Trine H Mogensen
  • Maria H Christensen, Institute of Innate Immunity, Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn 53127, Germany.
  • ,
  • Jens R Nyengaard
  • Ganes C Sen, Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • ,
  • Henrik Zetterberg, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Health and Caring Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden.
  • ,
  • Georges Mgm Verjans, Department of Viroscience
  • ,
  • Søren R Paludan

Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.

Original languageEnglish
JournalJournal of Clinical Investigation
Volume131
Issue1
ISSN0021-9738
DOIs
Publication statusPublished - 4 Jan 2021

See relations at Aarhus University Citationformats

ID: 207859789