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

Line S Reinert1, Ahmad S Rashidi2, Diana N Tran2, Georgios Katzilieris-Petras1, Astrid K Hvidt1, Mette Gohr1, Stefanie Fruhwürth3, Chiranjeevi Bodda1, Martin K Thomsen1, Mikkel H Vendelbo1, Ahmad Raza Khan4, Brian Hansen4, Petra Bergström3, Lotta Agholme3, Trine H Mogensen1, Maria H Christensen5, Jens R Nyengaard6, Ganes C Sen7, Henrik Zetterberg8, Georges Mgm Verjans9, Soren R Paluden1

  1. Department of Biomedicine, University of Aarhus, Århus, Denmark.
  2. Department of Viroscience, Erasmus Medical Centre, Rotterdam, Netherlands.
  3. Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
  4. Center of Functionally Integrative Neuroscience (CFIN), University of Aarhus, Århus, Denmark.
  5. Institute of Innate Immunity, University of Bonn, Bonn, Germany.
  6. Department of Clinical Medicine, University of Aarhus, Århus, Denmark.
  7. Department of Immunology, Cleveland Clinic, Cleveland, United States of America.
  8. Institute of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden.
  9. Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.

Abstract

Protection of the brain from viral infections involves the type I interferon (IFN-I) system, defects in which renders humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels leads 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 here show that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, while 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 caspase inhibitor, exhibited lower viral load and improved outcome of infection. Collectively, we identify an activation-induced apoptosis program in brain immune cells which down-modulates local immune responses.

Presented By Line Reinert | ORCID iD

Immunology & MicrobiologyNicholas Liao2020-09 (Sep)