Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production
Line S. Reinert, … , Georges MGM Verjans, Søren R. Paludan
Line S. Reinert, … , Georges MGM Verjans, Søren R. Paludan
Published September 29, 2020
Citation Information: J Clin Invest. 2021;131(1):e136824. https://doi.org/10.1172/JCI136824.
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Research Article Immunology Infectious disease

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

Abstract

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.

Authors

Line S. Reinert, Ahmad S. Rashidi, Diana N. Tran, Georgios Katzilieris-Petras, Astrid K. Hvidt, Mette Gohr, Stefanie Fruhwürth, Chiranjeevi Bodda, Martin K. Thomsen, Mikkel H. Vendelbo, Ahmad R. Khan, Brian Hansen, Petra Bergström, Lotta Agholme, Trine H. Mogensen, Maria H. Christensen, Jens R. Nyengaard, Ganes C. Sen, Henrik Zetterberg, Georges MGM Verjans, Søren R. Paludan

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Figure 1

HSV-1 induces cGAS-dependent cell death in the brain microenvironment.

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HSV-1 induces cGAS-dependent cell death in the brain microenvironment. B...
Brainstems were isolated at 5 days after HSV-1 infection via the corneal route (2 × 106 PFU/cornea). (A) IFN/ISG profiles from samples isolated by laser-capture microdissection (LCM). Relative transcript levels of the indicated genes in areas of the brainstem from mock- or HSV-1–infected C57Bl/6 mice. The red box indicates degree of infection in the infected brainstem areas subjected to LCM based on IHC staining of the sequential sections. Values are normalized to β-actin and each row represents 1 LCM preparation (n = 4–8 mice per group). Blue and red color indicate low and high expression, respectively. (B) IHC images of brainstems from HSV-1–infected mice stained for TUNEL (green) and HSV-1 VP5 (red). Scale bar: 10 μm. Areas marked by squares are magnified in the images to the right of the large images. Animals per group: n = 6–7.