RAGE engagement by SARS-CoV-2 enables monocyte infection and underlies COVID-19 severity
Roberta Angioni, Matteo Bonfanti, Nicolò Caporale, Ricardo Sánchez‐Rodríguez, Fabio Munari, Aurora Savino, Sebastiano Pasqualato, Damiano Buratto, Isabel Pagani, Nicole Bertoldi, Carlo Zanon, Paolo Ferrari, Eugenia Ricciardelli, Cristina Putaggio, Silvia Ghezzi, Francesco Elli, Luca Rotta, Alessandro Scardua, Janine Weber, Valentina Cecatiello, Francesco Iorio, Francesco Zonta, Anna Maria Cattelan, Elisa Vicenzi, Alessandro Vannini, Barbara Molon, Carlo Emanuele Villa, Antonella Viola, Giuseppe Testa
Abstract
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.