SARS-CoV-2 infection of the brain: the K18-hACE2 mouse model to illustrate the role and response of the vasculature in neurotropic viral infection

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract and lungs; however, the associated disease, coronavirus disease 2019 (COVID-19) can also involve the central nervous system. The pathomechanisms underlying neurological impairments in COVID-19 and post COVID-19 condition remain incompletely understood, hence experimental studies under defined conditions, in a suitable animal model, can help to clarify the effect of SARS-CoV-2 infection in the brain. The K18-hACE2 mouse represents such a model, as intranasal challenge with SARS-CoV-2 VOC generally results in widespread neuronal infection with limited tissue response in the brain, consistent with a mild non-suppurative (meningo)encephalitis, with microgliosis, astrogliosis and (peri)vascular leukocyte infiltrates but no evidence of infection of vessel structures. The present study used this model to address the hypothesis that the vascular reaction is secondary to the neuronal infection. It confirmed that in intranasally challenged K18-hACE2 mice the virus targeted the neurons without overt neuropathic effect, whilst sparing the blood vessels, and further characterised the resulting inflammatory response in the brain in situ and through bulk RNA sequencing. The former highlighted the recruitment of leukocytes (neutrophils, monocytes/macrophages, and lymphocytes) via postcapillary venules, with their accumulation in the perivascular space and occasional emigration into the neuroparenchyma, without targeting and/or damage to the vessel wall. At the transcriptome level, this was accompanied by positive enrichment of pathways and the upregulation of genes involved in both the inflammatory reaction and the recruitment (including adhesion and migration) and activity of the leukocytes. We also found morphological and molecular evidence of subtle impairment of blood-brain barrier function, i.e. increased permeability. The results obtained from the model indicate that SARS-CoV-2 infection of the neurons induces neuroinflammation, with leukocyte recruitment and activation as well as blood-brain barrier dysfunction. These data can help to understand more fully the reaction of the CNS in COVID-19 patients, and neurotropic virus infections in general.