Long COVID in K18-hACE2 mice causes persistent brain inflammation and cognitive impairment

Abstract Evidence suggests that patients with long COVID experience cognitive abnormalities. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent neurological symptoms are unknown. Here we establish an animal model of long COVID by eliciting mild disease in K18-hACE2 mice. Following recovery from infection with a low dose of SARS-CoV-2, K18-hACE2 mice show the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also have elevated expression of B1Rs and inflammatory markers in the brain and exhibit cognitive impairments such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential of this model for investigating long COVID. The results further imply that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection.