The link between microglia and the severity of COVID-19: the 'two-hit' hypothesis.
Increasing evidence suggests that neurological manifestations constitute an important cause of morbidity and mortality in the new coronavirus-disease 2019 (COVID-19). This is in line with a significant role of the microglia, the brain-resident macrophages of the CNS, as highlighted in severe cases of COVID-19. Vulnerability of individuals to the severe acute respiratory syndrome coronavirus (SARS-CoV-2) could be explained by hyperactive microglia primed or sensitized following a previous stimulation that may date back to earlier insults in life, which results in an exaggerated response to coronavirus infection. In this 'two-hit' hypothesis, aging, psychological stressors, early-life stressor events, and chronic diseases are considered as the first priming hit that pre-active microglia. Whereas, coronavirus infection, the following immune challenge (the second hit), leads to uncontrolled pro-inflammatory response that will have significant consequences on brain and health, and may explain inter-individual differences in the reaction to SARS-CoV-2, including severe symptoms in particular in older patients or those with co-morbidity. The involvement of microglia would also point out toward potential pre-screening and therapeutic approaches in order to detect higher susceptibility of COVID-19 patients to severe disease trajectories. This article is protected by copyright. All rights reserved.