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

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  • Line S Reinert
  • Ahmad S Rashidi, Erasmus Medical Centre, 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, 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, University of Bonn
  • ,
  • 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.

OriginalsprogEngelsk
Artikelnummere136824
TidsskriftJournal of Clinical Investigation
Vol/bind131
Nummer1
Antal sider18
ISSN0021-9738
DOI
StatusUdgivet - jan. 2021

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