SARS-CoV-2 Is Literally Killing The Microglia Cells In The Host Brain


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.

Patients with more severe infection are more likely to have neurological manifestations and impairment and are at a higher risk of mortality (15).

Microglia are macrophage-like brain’s immune cells in the central nervous system (CNS). They have key functions in maintaining brain homeostasis and in the rapid response to injury and inflammation (16). When microglia respond to immunological stimuli, they become activated and transform from a ramified into an amoeboid morphology, releasing interleukin (IL)-1β, IL-6, and tumour necrosis α (TNF-α) (17).

Activated microglia consist of a dual phenotype, wherein M1 or the classically activated state is neurotoxic and involved in neuroinflammation, and M2 or the alternatively activated state is neuroprotective (18-20).

Increasing evidence suggests that the over-activation and dysregulation of microglia might result in disastrous and progressive neurotoxic consequences (21-24).

In brains of deceased COVID-19 patients, microgliosis and immune cell accumulation were observed (25), as well as microglial nodules caused by massive microglia activation in the medulla oblongata (26) and cerebellar dentate nuclei (27). The neuroinvasive capacity (28) and olfactory transmucosal invasion of SARS-CoV-2 in COVID-19 patients (29) have also been reported.

Additionally, human microglia express SARS-CoV-2 entry factors such as angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) (30).

Thus, we hypothesised that microglial activation by direct SARS-CoV-2 infection could be one of the major mechanisms driving the neuroinflammation and neurological complications.

Despite accumulating evidence, little is known regarding the mechanisms involved in the neuroinflammation of SARS-CoV-2 infection. In this study, we demonstrated that SARS-CoV-2 can directly infect human microglia and induce pro-inflammatory responses, reflecting polarization toward the M1 phenotype.

We further showed that the SARS-CoV-2 infection led to apoptosis as the cytopathic effect (CPE) through both intrinsic and extrinsic apoptotic pathways. Moreover, we found that murine microglia expressing hACE2 were infected by intranasally administered SARS-CoV-2, followed by microglial pro-inflammatory activation and loss of their population.

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