SARS-CoV-2 causes brain inflammation via impaired neuro-immune interactions

The brain inflammation that frequently occurs in SARS-CoV-2 is the cause of neurological complications1,2 and long COVID 3,4,5. However, many aspects of its pathogenesis mechanism remain unknown 6, 7 and no method of treatment has been established 8. By administering a non-proliferating adenovirus vector expressing SARS-CoV-2 S1 protein into the nasal cavity of mice, we developed a mouse model (S1 mouse) reproducing brain inflammation, fatigue, depressive symptoms, and lung inflammation. Having intracellular calcium elevating activity, S1 protein increased olfactory bulb apoptosis, and reduced the number of acetylcholine producing cells in the medial septal and the diagonal band of Broca as well as the amount of acetylcholine in the brain. This resulted in disrupting the cholinergic anti-inflammatory pathway (CAP) 9 and enhancing inflammation in the brain. Previously, nothing was known about anti-inflammatory factors in the CAP but we discovered that, in the inflammation occurring in the S1 mouse brain, the action of the RNA binding protein ZFP36 10 in degrading inflammatory cytokine mRNA was impaired. The symptoms exhibited by the S1 mouse were improved by administering donepezil, a drug with a cholinergic action used in the treatment of dementia. These findings clarify the mechanism of brain inflammation in COVID-19 and indicate the possibility of applying donepezil in the treatment of neurological complications in COVID-19 and long COVID.