Human serum albumin binds spike protein and protects cells from SARS-CoV-2 infection by modulating the RAS pathway

Abstract

Human serum albumin binds spike protein and protects cells from SARS-CoV-2 infection by modulating the RAS pathway Romualdo Varricchio a,1, Giovanna De Simone a,1, Gian Marco Vita a, Walter Nocera Cariola a, Maurizio Viscardi b, Sergio Brandi b, Gerardo Picazio b, Verena Zerbato c, Raffaella Koncan d,e, Ludovica Segat d, Stefano Di Bella e, Giovanna Fusco b, Paolo Ascenzi a, Alessandra di Masi a,* a Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, 00146 Roma, Italy b Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici (NA), Italy c Infectious Diseases Unit, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), 34128 Trieste, Italy d Unit`a Complessa Operativa Igiene e Sanit`a Pubblica, Azienda Sanitaria Universitaria Integrata Giuliano Isontina (ASUGI), Trieste, Italy e Clinical Department of Medical, Surgical and Health Sciences, Trieste University, 34149 Trieste, Italy A R T I C L E I N F O Keywords: ACE2 Human serum albumin Renin-angiotensin pathway SARS-CoV-2 S1 domain Spike A B S T R A C T Since the start of the pandemic, scientists have directed their research towards identifying COVID-19 risk factors and predictive elements. Numerous clinical studies have established a strong connection between hypoalbuminemia and an unfavorable prognosis for COVID-19. Here, we aim to explore the impact of human serum albumin (HSA) on SARS-CoV-2 infection. Our findings indicate that HSA plays a role in reducing the replication rate of SARS-CoV-2 in Vero E6 cells. This protective effect is due to HSA ability to bind to the S1 domain of the spike protein, effectively competing with ACE2. Moreover, we show that the protective role of HSA is dependent also on its ability to activate the protective axis within the RAS system pathway, which is responsible for inducing vasodilation and promoting anti-inflammatory, anti-fibrotic, and anti-apoptotic responses. In summary, the data presented in this study support the idea that reduced levels of circulating HSA in hypoalbuminemic patients may heighten their susceptibility to SARS-CoV-2 infection, as the spike protein is unhindered in its ability to bind to ACE2 and penetrate human cells. Besides, hypoalbuminemia exacerbates the imbalance of the RAS pathway towards the classical “detrimental” axis. This could potentially contribute to the increased severity and elevated mortality rate observed in individuals with low levels of circulating albumin.