tetano
Editor, Senior Moderator
Microbiol Spectr
. 2022 May 5;e0109122.
doi: 10.1128/spectrum.01091-22. Online ahead of print.
SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death
Gi Uk Jeong[SUP] 1 [/SUP], Jaemyun Lyu[SUP] 2 [/SUP], Kyun-Do Kim[SUP] 1 [/SUP], Young Cheul Chung[SUP] 3 [/SUP], Gun Young Yoon[SUP] 1 [/SUP], Sumin Lee[SUP] 1 [/SUP], Insu Hwang[SUP] 1 [/SUP], Won-Ho Shin[SUP] 3 [/SUP], Junsu Ko[SUP] 2 [/SUP], June-Yong Lee[SUP] 4 5 [/SUP], Young-Chan Kwon[SUP] 1 [/SUP]
Affiliations
Abstract
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.
Keywords: M1 polarization; SARS-CoV-2; apoptosis; microglia; neuroinflammation.
. 2022 May 5;e0109122.
doi: 10.1128/spectrum.01091-22. Online ahead of print.
SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death
Gi Uk Jeong[SUP] 1 [/SUP], Jaemyun Lyu[SUP] 2 [/SUP], Kyun-Do Kim[SUP] 1 [/SUP], Young Cheul Chung[SUP] 3 [/SUP], Gun Young Yoon[SUP] 1 [/SUP], Sumin Lee[SUP] 1 [/SUP], Insu Hwang[SUP] 1 [/SUP], Won-Ho Shin[SUP] 3 [/SUP], Junsu Ko[SUP] 2 [/SUP], June-Yong Lee[SUP] 4 5 [/SUP], Young-Chan Kwon[SUP] 1 [/SUP]
Affiliations
- PMID: 35510852
- DOI: 10.1128/spectrum.01091-22
Abstract
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.
Keywords: M1 polarization; SARS-CoV-2; apoptosis; microglia; neuroinflammation.