In vivo characterization of ACE2 expression in Sprague-Dawley rats and cultured primary brain pericytes highlights the utility of Rattus norvegicus in the study of COVID-19 brain pathophysiology.

Abstract

A high number of COVID-19 patients report ongoing neurological impairments including headache, fatigue and memory impairments. Our understanding of COVID-19 disease mechanisms in the brain is limited and relies on post-mortem human tissues, in vitro studies in various cell lines (both human and animal) as well as preclinical studies in a variety of species. Notably the use of rats in the study of COVID-19 has been scarce in part due to early reports of low infectivity of the original Wuhan strain in mice and rats. Evidence has shown that subsequent strains that have mutated from the original strain and are capable of infection in rats. Here we present an immunohistological characterization of ACE2 expression in the rat brain perivascular region. We found ACE2 to be expressed in pericytes but not endothelial cells or astrocytes in the perivascular space. We further examined the uptake of Omicron variants 1.1.529 and BA.2 receptor binding domains (RBD) of the SARS-CoV2 spike protein in primary brain pericytes derived from rats. We demonstrate that rat primary brain pericytes are susceptible to SARS-CoV2 spike protein uptake and induce functional changes in pericytes associated with a reduction in tight junction protein expression. These data provide evidence that rat primary cell responses to SARS-CoV2 infection are consistent with reports of infectivity in other species (transgenic mice expressing hACE2, ferrets, hamsters) and supports the use of this model organism with a long history of use in the study of disease which should be leveraged for study of COVID-19 in the brain.