RESUMEN
Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.
Asunto(s)
COVID-19/genética , Diabetes Mellitus/genética , MicroARNs/genética , Glicoproteína de la Espiga del Coronavirus/genética , Adulto , Factores de Edad , Anciano , COVID-19/sangre , COVID-19/patología , COVID-19/virología , China , MicroARN Circulante/sangre , MicroARN Circulante/genética , Estudios de Cohortes , Diabetes Mellitus/sangre , Diabetes Mellitus/patología , Diabetes Mellitus/virología , Ejercicio Físico , Exosomas/genética , Exosomas/metabolismo , Exosomas/virología , Femenino , Regulación de la Expresión Génica , Células HEK293 , Interacciones Huésped-Patógeno/genética , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , SARS-CoV-2/genética , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/sangre , Replicación ViralRESUMEN
Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.