RESUMO
[Figure: see text].
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/fisiopatologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/fisiologia , Animais , Antígenos CD/metabolismo , COVID-19/complicações , Caderinas/metabolismo , Permeabilidade Capilar , Caspase 1/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Edema/fisiopatologia , Edema/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática , Fibrose/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neutrófilos/fisiologia , Circulação Pulmonar , Receptores de Interleucina-1/antagonistas & inibidores , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacosRESUMO
Blood-brain barrier (BBB) permeability can cause neuroinflammation and cognitive impairment. Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on the BBB and consequent neurological outcomes in respiratory viral infections is unknown. We used Cav-1-deficient mice with genetically encoded fluorescent endothelial tight junctions to determine how Cav-1 influences BBB permeability, neuroinflammation, and cognitive impairment following respiratory infection with mouse adapted (MA10) SARS-CoV-2 as a model for COVID-19. We found that SARS-CoV-2 infection increased brain endothelial Cav-1 and increased transcellular BBB permeability to albumin, decreased paracellular BBB Claudin-5 tight junctions, and caused T lymphocyte infiltration in the hippocampus, a region important for learning and memory. Concordantly, we observed learning and memory deficits in SARS-CoV-2 infected mice. Importantly, genetic deficiency in Cav-1 attenuated transcellular BBB permeability and paracellular BBB tight junction losses, T lymphocyte infiltration, and gliosis induced by SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results establish the contribution of Cav-1 to BBB permeability and behavioral dysfunction induced by SARS-CoV-2 neuroinflammation.