Modulating HMGB1 in COVID-19-associated inflammatory response
The project addresses urgent and clinically-relevant questions related to COVID-19, which causes in some patients life-threatening respiratory distress, septic shock and organ failures. Patients in intensive care units were found to have significantly higher levels of high mobility group box 1 (HMGB1) than patients with milder symptoms. HMGB1 is a protein normally found in the cell nucleus that is released outside the cell under inflammatory conditions such as viral infections. Although its role in COVID-19 pathology remains unclear, its levels in the blood are correlated to the severity of sepsis and organ dysfunction, and could contribute to the higher mortality rate observed in patients with other inflammatory conditions.
The reason for targeting HMGB1 in COVID-19 rests upon its key role as an inflammatory protein increased in COVID-19. Our main goal is to modulate its level and activity in COVID-19-associated inflammatory response using pharmacological and nanotherapeutical agents – JN2019, JN2020, fisetin and dPGS – which target different steps in HMGB1 regulation. COVID-19-associated inflammation will be modelled in human cells of organs most impacted by the virus (lungs, kidneys, brain) using the main viral protein (S-protein). Cell death resulting from excessive inflammation will be correlated to HMGB1 protein modifications and activity.