RESUMEN
Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.
Asunto(s)
Lesión Renal Aguda/orina , COVID-19/orina , Túbulos Renales Proximales/virología , Riñón/virología , Organoides/virología , SARS-CoV-2/patogenicidad , Lesión Renal Aguda/etiología , Adulto , Anciano , Enzima Convertidora de Angiotensina 2/genética , Animales , Apoptosis , Cápsula Glomerular/citología , Cápsula Glomerular/virología , COVID-19/complicaciones , Chlorocebus aethiops , Femenino , Técnicas de Inactivación de Genes , Mortalidad Hospitalaria , Hospitalización , Humanos , Riñón/metabolismo , Riñón/patología , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Masculino , Persona de Mediana Edad , Organoides/metabolismo , Podocitos/virología , Enfermedades Renales Poliquísticas , Proteína Quinasa D2/genética , Proteoma , Receptores de Coronavirus/genética , Reproducibilidad de los Resultados , Transcriptoma , Células Vero , Tropismo Viral , Replicación ViralRESUMEN
COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2.