RESUMEN
Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , COVID-19/metabolismo , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico/análisis , Receptores de Coronavirus/análisis , SARS-CoV-2/patogenicidad , Adulto , Anciano , Anciano de 80 o más Años , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Autopsia , COVID-19/mortalidad , COVID-19/patología , COVID-19/virología , Estudios de Casos y Controles , Chaperón BiP del Retículo Endoplásmico , Femenino , Interacciones Huésped-Patógeno , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Masculino , Persona de Mediana Edad , Proteostasis , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) initiates entry into airway epithelia by binding its receptor, angiotensin-converting enzyme 2 (ACE2). METHODS: To explore whether interindividual variation in ACE2 abundance contributes to variability in coronavirus disease 2019 (COVID-19) outcomes, we measured ACE2 protein abundance in primary airway epithelial cultures derived from 58 human donor lungs. RESULTS: We found no evidence for sex- or age-dependent differences in ACE2 protein expression. Furthermore, we found that variations in ACE2 abundance had minimal effects on viral replication and induction of the interferon response in airway epithelia infected with SARS-CoV-2. CONCLUSIONS: Our results highlight the relative importance of additional host factors, beyond viral receptor expression, in determining COVID-19 lung disease outcomes.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Receptores de Coronavirus/metabolismo , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/análisis , Variación Biológica Poblacional , Bronquios/citología , Bronquios/patología , Bronquios/virología , COVID-19/virología , Células Epiteliales , Femenino , Humanos , Masculino , Cultivo Primario de Células , Receptores de Coronavirus/análisis , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Mucosa Respiratoria/virología , Factores Sexuales , Internalización del VirusAsunto(s)
Envejecimiento/inmunología , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Inmunidad Adaptativa/inmunología , Adolescente , Adulto , Enzima Convertidora de Angiotensina 2/análisis , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/inmunología , COVID-19/diagnóstico , COVID-19/virología , Prueba de COVID-19 , Niño , Resfriado Común/inmunología , Resfriado Común/transmisión , Resfriado Común/virología , Proteínas de la Nucleocápside de Coronavirus/inmunología , Humanos , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , Fosfoproteínas/inmunología , Receptores de Coronavirus/análisis , Receptores de Coronavirus/metabolismo , Rhinovirus/inmunología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/virología , Linfocitos T/inmunología , Factores de Tiempo , Adulto JovenRESUMEN
Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.