RESUMEN
Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/genética , 2',5'-Oligoadenilato Sintetasa/metabolismo , COVID-19/genética , COVID-19/fisiopatología , ARN Bicatenario/metabolismo , ARN Viral/metabolismo , SARS-CoV-2/fisiología , Regiones no Traducidas 5' , Células A549 , Animales , COVID-19/enzimología , COVID-19/inmunología , Quirópteros/genética , Quirópteros/virología , Coronaviridae/enzimología , Coronaviridae/genética , Coronaviridae/fisiología , Endorribonucleasas/metabolismo , Humanos , Interferones/inmunología , Isoenzimas/genética , Isoenzimas/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Polimorfismo de Nucleótido Simple , Prenilación de Proteína , ARN Bicatenario/química , ARN Bicatenario/genética , ARN Viral/química , ARN Viral/genética , Retroelementos , SARS-CoV-2/genética , Índice de Severidad de la Enfermedad , Replicación ViralRESUMEN
Although high mortality has been reported in many COVID-19 studies, very limited postmortem information from complete autopsies is available. We report the findings in the adrenal glands in 28 autopsies with confirmed SARS-CoV-2 infection. Microscopic lesions were identified in the adrenal glands in 12/28 patients (46%). Seven cases showed necrosis, generally ischemic; four showed cortical lipid degeneration; two showed hemorrhage; and one unspecific focal adrenalitis. Vascular thrombosis in one patient and focal inflammation in association with other findings in three patients were observed. No case presented adrenal insufficiency. In conclusion, adrenal lesions are frequent in patients with severe COVID-19. The lesions are mild but could contribute to the lethal outcome.