RESUMEN
Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus-host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2. SCV2-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-2-5p play an important role in evasion of type I interferon response through targeting several genes in type I interferon signaling pathway. Particularly worth mentioning is that highly expressed SCV2-miR-ORF1ab-2-5p inhibits some key genes in the host innate immune response, such as IRF7, IRF9, STAT2, OAS1, and OAS2. SCV2-miR-ORF1ab-2-5p has also been found to mediate allelic differential expression of COVID-19-susceptible gene OAS1. In conclusion, these results suggest that SARS-CoV-2 uses its miRNAs to evade the type I interferon response and links the functional viral sequence to the susceptible genetic background of the host.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Evasión Inmune/genética , Interferón Tipo I/genética , SARS-CoV-2/genética , 2',5'-Oligoadenilato Sintetasa/genética , COVID-19/patología , Línea Celular , Células HEK293 , Interacciones Huésped-Patógeno/genética , Humanos , Inmunidad Innata/inmunología , Factor 7 Regulador del Interferón/genética , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , SARS-CoV-2/inmunología , Factor de Transcripción STAT2/genéticaRESUMEN
A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.
Asunto(s)
COVID-19/genética , COVID-19/inmunología , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Mutación con Pérdida de Función , SARS-CoV-2 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Factor 7 Regulador del Interferón/genética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Receptor Toll-Like 3/genética , Secuenciación del Exoma , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNß following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNß production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNß regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNß production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism's regulation of innate immune response.
Asunto(s)
Factor 7 Regulador del Interferón/genética , Interferón beta/genética , Glicoproteínas de Membrana/genética , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito/genética , Receptor Toll-Like 7/genética , Animales , Citocinas/genética , Humanos , Inmunidad Innata/genética , Interferón Tipo I/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , FN-kappa B/genética , Quinolonas/toxicidad , Factor de Transcripción AP-1/genéticaRESUMEN
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.