RESUMEN
[Figure: see text].
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/fisiopatología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Receptores de Interleucina-1/fisiología , Animales , Antígenos CD/metabolismo , COVID-19/complicaciones , Cadherinas/metabolismo , Permeabilidad Capilar , Caspasa 1/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Edema/fisiopatología , Edema/prevención & control , Endotelio Vascular/efectos de los fármacos , Activación Enzimática , Fibrosis/prevención & control , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neutrófilos/fisiología , Circulación Pulmonar , Receptores de Interleucina-1/antagonistas & inhibidores , SARS-CoV-2 , Transducción de Señal/efectos de los fármacosRESUMEN
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
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been demonstrated to limit the host interferon response; however, the underlying mechanism remains unclear. Here, we found that SARS-CoV-2 infection upregulated the E3 ubiquitin ligase Huwe1, which in turn facilitated the degradation of the transcription factor Miz1. The degradation of Miz1 hampered interferon alpha and gamma responses, consequently fostering viral replication and impeding viral clearance. Conversely, silencing or inhibiting Huwe1 enhanced the interferon responses, effectively curbing viral replication. Consistently, overexpressing Miz1 augmented the interferon responses and limited viral replication, whereas silencing Miz1 had the opposite effect. Targeting Huwe1 or overexpressing Miz1 elicited transcriptomic alterations characterized by enriched functions associated with bolstered antiviral response and diminished virus replication. Further study revealed Miz1 exerted epigenetic control over the transcription of specific interferon signaling molecules, which acted as common upstream regulators responsible for the observed transcriptomic changes following Huwe1 or Miz1 targeting. These findings underscore the critical role of the Huwe1-Miz1 axis in governing the host antiviral response, with its dysregulation contributing to the impaired interferon response observed during COVID-19.