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

 Gi Uk Jeong  ;  Jaemyun Lyu  ;  Kyun-Do Kim  ;  Young Cheul Chung  ;  Gun Young Yoon  ;  Sumin Lee  ;  Insu Hwang  ;  Won-Ho Shin  ;  Junsu Ko  ;  June-Yong Lee  ;  Young-Chan Kwon 
 MICROBIOLOGY SPECTRUM, Vol.10(3) : e0109122, 2022-06 
Journal Title
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Animals ; Apoptosis* ; COVID-19* ; Cell Line ; Cytokines / metabolism ; Humans ; Interleukin-6 ; Mice ; Mice, Transgenic ; Microglia* / virology ; SARS-CoV-2 ; Tumor Necrosis Factor-alpha
M1 polarization ; SARS-CoV-2 ; apoptosis ; microglia ; neuroinflammation
Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in patients with coronavirus disease 2019 (COVID-19). 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 reported that SARS-CoV-2 can directly infect human microglia, eliciting M1-like proinflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA sequencing (RNA-seq) analysis also revealed that endoplasmic reticulum (ER) stress and immune responses were induced in the early, and apoptotic processes in the late phases of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α), but not the anti-inflammatory cytokine IL-10. After this proinflammatory 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 proinflammatory 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 patients with COVID-19. IMPORTANCE Recent studies reported neurological and cognitive sequelae in patients with COVID-19 months after the viral infection with several symptoms, including ageusia, anosmia, asthenia, headache, and brain fog. Our conclusions raise awareness of COVID-19-related microglia-mediated neurological disorders to develop treatment strategies for the affected patients. We also indicated that HMC3 was a novel human cell line susceptible to SARS-CoV-2 infection that exhibited cytopathic effects, which could be further used to investigate cellular and molecular mechanisms of neurological manifestations of patients with COVID-19.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Lee, June-Yong(이준용)
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