Abstract
COVID-19 has attracted global attention due to its rapid spread around the world with substantial morbidity and associated mortality. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock leading to death. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure. Here, we report that high mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) and a central mediator of lethal inflammation, could be a potential target for innovative therapeutic strategies for COVID-19. Serum HMGB1 in severe COVID-19 patients is elevated (189.40 ± 140.88 ng/ml). Exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner. Importantly, genetic (using AGER siRNA) or pharmacological (using glycyrrhizin, chloroquine, hydroxychloroquine, and FPS-ZM1) inhibition of the HMGB1-AGER pathway blocks ACE2 expression. Thus, HMGB1 inhibitors are likewise promising drug candidates for the treatment of patients suffering from COVID-19.
Highlights
In the past 20 years, humans have suffered from three coronaviruses outbreaks, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and the ongoing outbreak of the coronavirus disease 2019 (COVID-19) caused by a new virus SARS-CoV-2 [1]
The information gathered from these case studies indicates that serum high mobility group box 1 (HMGB1) in COVID-19 patients positively correlated with disease severity
COVID-19 is a life-threatening viral infection caused by the host's abnormal response to SARS-CoV-2, which is closely related to sepsis and septic shock [1]
Summary
In the past 20 years, humans have suffered from three coronaviruses outbreaks, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and the ongoing outbreak of the coronavirus disease 2019 (COVID-19) caused by a new virus SARS-CoV-2 [1]. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock, leading to death [6]. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure [7]. Damage-associated molecular pattern molecules (DAMPs) are endogenous ‘alarmin’ molecules that are released from dead or damaged cells, activating the immune system by interacting with several pattern recognition receptors, including toll-like receptors (TLR2, TLR4, and TLR9) and the advanced glycosylation end-product specific receptor (AGER, known as RAGE) [8, 9]
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