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 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.

Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms

“…However, high viral load in the CNS produces an interesting phenotype in non–neuronal cells that is mediated by cGAS–STING signaling. More specifically, mice with herpes simplex encephalitis (HSE) exhibited increased apoptosis of microglia (brain–specific immune cells) ( 165 ). The apoptotic response appears to be independent of IFN–1 signaling, as IFNAR–deficient mice demonstrate an increased susceptibility to HSV–1, while not demonstrating less apoptosis of immune cells.…”

“…The apoptotic response appears to be independent of IFN–1 signaling, as IFNAR–deficient mice demonstrate an increased susceptibility to HSV–1, while not demonstrating less apoptosis of immune cells. In addition, apoptosis appears to be specific to microglia and other immune cells, as neurons and other neuronal cell types do not demonstrate the same degree of apoptosis as immune cells ( 165 ). Although this apoptotic response was initially observed in mice, apoptosis of immune cells was also observed in human organotypic cell culture and in tissue obtained from patients who had succumbed from HSE ( 165 ).…”

“…In addition, apoptosis appears to be specific to microglia and other immune cells, as neurons and other neuronal cell types do not demonstrate the same degree of apoptosis as immune cells ( 165 ). Although this apoptotic response was initially observed in mice, apoptosis of immune cells was also observed in human organotypic cell culture and in tissue obtained from patients who had succumbed from HSE ( 165 ). The exact mechanism responsible for activation of apoptosis through cGAS–STING signaling is yet to be elucidated.…”

“…The exact mechanism responsible for activation of apoptosis through cGAS–STING signaling is yet to be elucidated. It is thought that the apoptotic response in immune cells may function as a regulator of IFN–1 expression by the cGAS–STING signaling pathway ( 165 ). When the viral load during HSV–1 infection is low, local immune cells can produce IFN–1 via DNA sensing through cGAS–STING.…”

Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses

“…Circadian behaviour was accessed during a period of light/dark cycle and under constant darkness as previously described (Abitbol et al, 2017). HSV-1 brain infections in mice were conducted as previously described (Reinert et al, 2021).…”