Direct interaction of HMGB1 with SARS-CoV-2 facilitates its infection via RAGE-dependent endocytosis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused >770 million infections since 2020. SARS-CoV-2 outcomes are largely influenced by host immune responses. Among key mediators of innate immunity, high-mobility group box 1 (HMGB1) has gained attention for its role in inflammation during SARS-CoV-2 infection, and its levels are significantly elevated in acute and post-COVID-19 cases, correlating with disease severity. This study investigated the role of HMGB1 in COVID-19 pathogenesis. Our findings demonstrate that the SARS-CoV-2 spike protein directly interacts with HMGB1, forming an HMGB1-SARS-CoV-2 complex. This complex interacts with the receptor for advanced glycation end-products (RAGE), facilitating clathrin-mediated endocytosis and enhancing SARS-CoV-2 infection in human lung cells <i>in vitro</i> and in mouse models of infection. Overall, this study demonstrates the role of HMGB1 in promoting viral entry via RAGE, emphasizing its potential as a therapeutic target in severe COVID-19 cases.