Role of HMGB1 in the activation of innate immune responses during SARS-CoV-2 infection

Abstract The ongoing COVID-19 pandemic caused by SARS-CoV-2 has resulted in overwhelming number of deaths worldwide, affecting all age groups. Due to the emergence and rapid spread of SARS-CoV-2 variants and waning immunity in humans to current vaccines, it is imperative that new treatment modalities must continue to be developed for combating this deadly disease. The molecular mechanisms by which SARS-CoV-2 increases risk of serious respiratory disease is largely unknown but exuberant lung inflammatory and immune responses are key. Understanding of the cascades of events that initiate and sustain inflammatory processes contributing to more severe disease is crucial for developing effective therapies for COVID-19. In this study, we found that the release of high-mobility group box 1 (HMGB1), a proinflammatory mediator that alerts the immune system, was increased in the medium of human lung epithelial cells (A549-ACE2 and Calu-3/2B4) in vitro infected with SARS-CoV-2, and in the serum of SARS-CoV-2 infected mice and humans. Our studies showed that SARS-CoV-2 induced acute inflammation by downregulating the retinoic acid inducible gene-I (RIG-I)-dependent interferon (IFN)-mediated innate antiviral immune response and nuclear factor erythroid 2-related factor (NRF2)-dependent antioxidant mechanism. Treatment with rHMGB1 significantly activated the innate antiviral and antioxidant pathways and inhibited the viral replication. Our studies demonstrated an important role of HMGB1 in the regulation of viral replication and cellular protection as well as the activation of innate immune signaling cascades to promote inflammation. Modulation of HMGB1’s proinflammatory signaling may attenuate SARS-CoV-2-induced lung inflammation. This work was supported by COVID-19 and Emerging Respiratory Viruses Research Award from American Lung Association (COVID-920427), COVID-19 Bridging grant from Sealy Institute for Vaccine Sciences (C28455), Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI) (grant I.D. number 123385), NIH/NIAID R21 AI35619, Short-Term Provost’s Scholar Award by CTSA Mentored Career Development Award, CTSA KL2 COVID Funds (NIH/NCATS KL2TR001441) to YMH.