SARS-CoV-2 Infection of Microglia Elicits Pro-inflammatory Activation and Apoptotic Cell Death

Abstract

Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in coronavirus disease 2019 (COVID-19) patients. The most dominant immune cells in the brain are microglia. Yet, the relationship between neurological manifestations, neuroinflammation, and host immune response of microglia to SARS-CoV-2 has not been well characterized. Here, we report that SARS-CoV-2 can directly infect human microglia, eliciting M1-like pro-inflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA-seq analysis also revealed that ER stress and immune responses were induced in the early and apoptotic processes in the late phase of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumour necrosis factor α (TNF-α), but not the anti-inflammatory cytokine IL-10. After this pro-inflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of pro-inflammatory microglial IL- 6 and TNF-α and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in COVID-19 patients.

Non-Productive Infection of Glial Cells with SARS-CoV-2 in Hamster Organotypic Cerebellar Slice Cultures

“…Therefore, further studies that closely examine SARS-CoV-2 localization in astrocytic processes and/or brain microvasculature may help shed further light on SARS-CoV-2 neuroinvasiveness. We also observed rare infection of IBA + microglia; microglial infection was also recently reported by Jeong et al in a study that is available as a pre-print [41].…”

Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in Post-Acute COVID-19 syndrome—A narrative review

“…Activated microglia become ameboid-shaped and express ACE2 and transmembrane protease serine subtype 2 (TMPRSS2) ( Singh, Bansal & Feschotte, 2020 ). A recent study has shown that microglia are directly infected by the SARS-COV-2 virus and can cause self-apoptosis, thereby causing a reduction in the number of microglia which leads to further infiltration of the virus ( Jeong et al, 2022 ). Secondly, infection with SARS-COV-2 significantly increased the level of TNF-α and IL-6, suggesting that activated microglia lead to neuroinflammation ( Jeong et al, 2022 ).…”

“…A recent study has shown that microglia are directly infected by the SARS-COV-2 virus and can cause self-apoptosis, thereby causing a reduction in the number of microglia which leads to further infiltration of the virus ( Jeong et al, 2022 ). Secondly, infection with SARS-COV-2 significantly increased the level of TNF-α and IL-6, suggesting that activated microglia lead to neuroinflammation ( Jeong et al, 2022 ). A Post-mortem study of brains of patients deceased from COVID-19 showed neuropathological signs of microglial activation ( Matschke et al, 2020 ).…”

Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells

“…Our study has limitations that must be considered. Firstly, we focused exclusively on the airway epithelium, and it is now established that SARS-CoV-2 is capable of infecting other cell lineages including monocytes, monocyte-derived macrophages, and microglia (Boumaza et al, 2021;Jeong et al;Liu et al, 2021). It is possible that Gal-9 does not exert similar effects on viral replication or immune signaling in other target cell types.…”