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

Ling Yan,Li Tian,Keerthana Chithanathan,Alexander Zharkovsky,Mohan Jayaram

doi:10.3389/fncel.2021.750373

Abstract

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 (Ace2) and basigin (Bsg) 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 FURIN and neuropilin-1 (NRP1) 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.

Highlights

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been giving a significant psychosocial impact on human beings leading to our prolonged state of mental stress (Saladino et al, 2020)
We found that the abundancy of microglia, especially MHCII+ microglia in the hippocampus and mRNA levels of angiotensin-converting enzyme 2 (Ace2) and Bsg in the prefrontal cortex (PFC), was upregulated only in stressed female mice but not in males
Using the Brain explorer R 2 software, we further scrutinized the spatial distributions of these genes within the PFC areas, namely the anterior cingulate cortex, prelimbic area, infralimbic area, and orbital area, and we found their overall enrichment in the orbital area except Ace2, as summarized in Supplementary Table 2

Summary

Introduction

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been giving a significant psychosocial impact on human beings leading to our prolonged state of mental stress (Saladino et al, 2020). The main host cell receptor for the SARS-CoV-2 virus is angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al, 2020; Yang et al, 2020). Neuropilin-1 (NRP1) and Furin assist ACE2 in viral attachment (Xia et al, 2020) These viral receptors are expressed by different cell types including brain cells (Fodoulian et al, 2020; Vargas et al, 2020; Chen et al, 2021) and can be regulated by neurological pathologies (Davies et al, 2020; Fodoulian et al, 2020; Qiao et al, 2020). The cerebral entry routes of the virus are suggested to possibly include the vasculature, the olfactory and trigeminal nerves, the cerebrospinal fluid, and the lymphatic system (Desforges et al, 2019; Boldrini et al, 2021)

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Results

Conclusion