biostudies-literatureAngioni RFondazione Città della Speranza101266https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694673biostudies-literatureUnknown4(11)The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes. In vitro THP1-based experiments indicate that monocytes bind the SARS-CoV-2 S1-receptor binding domain (RBD) via RAGE, pointing to RAGE-Spike interaction enabling monocyte infection. Thus, our results demonstrate that RAGE is a functional receptor of SARS-CoV-2 contributing to COVID-19 severity.Cell reports. MedicineRAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity.PMC1069467320/02CoVViola APasqualato SBuratto DElli FRotta LScardua AZonta FBonfanti MSavino ACattelan AMCaporale NGhezzi SFerrari PMolon BPutaggio CSanchez-Rodriguez RRicciardelli EPagani IBertoldi NWeber JVilla CEMunari FVicenzi EZanon CIorio FAngioni RCecatiello VVannini ATesta GfalseRAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity.The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes. In vitro THP1-based experiments indicate that monocytes bind the SARS-CoV-2 S1-receptor binding domain (RBD) via RAGE, pointing to RAGE-Spike interaction enabling monocyte infection. Thus, our results demonstrate that RAGE is a functional receptor of SARS-CoV-2 contributing to COVID-19 severity.2023-01-01T00:00:00Z2023 Nov2026-05-28T08:59:55.83Z2025-02-19T04:25:41.579ZS-EPMC106946733794453010.1016/j.xcrm.2023.101266