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.
https://journals.asm.org/doi/10.1128/spectrum.01091-22 |