RESUMEN
Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo. This analysis revealed significant suppression of Wnt/ß-catenin signalling, a critical regulator of blood-brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/ß-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected BBB integrity, reduced T-cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/ß-catenin signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections.
Asunto(s)
Barrera Hematoencefálica , COVID-19 , Disfunción Cognitiva , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Proteínas Wnt , Animales , Barrera Hematoencefálica/metabolismo , COVID-19/complicaciones , Ratones , Proteínas Wnt/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Vía de Señalización Wnt/fisiología , Ligandos , SARS-CoV-2 , Masculino , Encéfalo/metabolismoRESUMEN
Multiple sclerosis (MS) exhibits poor immune regulation and subnormal interferon (IFN-ß) signaling. Secondary Progressive MS displays waning exacerbations, relentless neurodegeneration, and diminished benefit of therapy. We find dysregulated serum protein balance (Th1/Th2) and excessive gene expression in Relapsing-Remitting MS vs. healthy controls (8700 differentially-expressed genes, DEG) and intermediate levels in SPMS (3900 DEG). Olfactory receptor genes (chemosensing), and WNT/ß-catenin (anti-inflammatory, repair) and metallothionein (anti-oxidant) gene pathways, have less expression in SPMS than RRMS. IFN-ß treatment decreased pro-inflammatory and increased metallothionein gene expression in SPMS. These gene expression biomarkers suggest new targets for immune regulation and brain repair in this neurodegenerative disease.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Humanos , Interferones , Biomarcadores , Metalotioneína/genéticaRESUMEN
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.
Asunto(s)
COVID-19 , Disfunción Cognitiva , Animales , Ratones , Barrera Hematoencefálica/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Disfunción Cognitiva/etiología , COVID-19/complicaciones , Trastornos de la Memoria/etiología , Enfermedades Neuroinflamatorias , Permeabilidad , SARS-CoV-2/metabolismoRESUMEN
Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with 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 indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.