HMGB1 as a potential biomarker and therapeutic target for severe COVID-19

Ruochan Chen; Yan Huang; Jun Quan; Jiao Liu; Haichao Wang; Timothy R Billiar; Michael T Lotze; Herbert J Zeh; Rui Kang; Daolin Tang

doi:10.1016/j.heliyon.2020.e05672

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19

Heliyon. 2020 Dec 7;6(12):e05672. doi: 10.1016/j.heliyon.2020.e05672. eCollection 2020 Dec.

Authors

Ruochan Chen^{1

2}, Yan Huang^{1

2}, Jun Quan^{1

2}, Jiao Liu³, Haichao Wang⁴, Timothy R Billiar⁵, Michael T Lotze⁵, Herbert J Zeh⁶, Rui Kang⁶, Daolin Tang⁶

Affiliations

¹ Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
² Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ The Third Affiliated Hospital, Guangzhou Medical University, Guangdong 510600, China.
⁴ Laboratory of Emergency Medicine, North Shore University Hospital, Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
⁵ Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
⁶ Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.

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.

Keywords: COVID-19; Cell culture; Cell death; HMGB1; Immunology; Infectious disease; Inflammation; Microbiology; Virology.