Sex-Specific Microglial Activation and SARS-CoV-2 Receptor Expression Induced by Chronic Unpredictable Stress.

The coronavirus disease 2019 (COVID-19) pandemic has generated a lot of stress and anxiety among not only infected patients but also the general population across the globe, which disturbs cerebral immune homeostasis and potentially exacerbates the SARS-CoV-2 virus-induced neuroinflammation, especially among people susceptible to neuropsychiatric disorders. Here, we used a chronic unpredictable mild stress (CUMS) mouse model to study its effects on glia-mediated neuroinflammation and expression of SARS-CoV2 viral receptors. We observed that female mice showed depressive-like behavior after CUMS, whereas male mice showed enhanced anxiety and social withdrawal. Interestingly, CUMS led to increased amounts of total and MHCII microglia in the hippocampi of female mice but not male mice. mRNA levels of SARS-CoV-2 viral receptors angiotensin-converting enzyme 2 () and basigin () were also upregulated in the prefrontal cortices of stressed female mice but not male mice. Similarly, sex-specific changes in SARS-CoV-2 viral receptors and neuropilin-1 () were also observed in monocytes of human caregivers enduring chronic stress. Our findings provided evidence on detrimental effects of chronic stress on the brain and behavior and implied potential sex-dependent susceptibility to SARS-CoV-2 infection after chronic stress.