Unraveled roles of hyaluronan in severe COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is a pandemic viral pneumonia caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). Most of the severe COVID-19 patients come up with trouble breathing, persistent pressure in the chest and developing to acute respiratory distress syndrome (ARDS) with a high mortality rate. Infected lung brings about uncontrolled inflammation followed by the fluid leakage and accumulation of extracellular matrix. Hyaluronan (HA) is an essential component of the extracellular matrix (ECM) and plays crucial roles in both biological and pathological states. It is also primarily located within the respiratory airways and is uprising during COVID-19 infection. Hitherto, the association between COVID-19 pathophysiology and HA is still unclear. Herein, we provide an overview of the pathophysiology of SARS-CoV-2 infection in conjunction with the involvement of HA and the diminution of HA for therapeutic potential of COVID-19. For severe patients, HA depletion may be beneficial for preventing ARDS while monitoring and managing HA level in lung may improve survival rate of patients.

Keywords: 4-methylumbelliferone; COVID-19; SARS-CoV-2; acute respiratory distress syndrome; cytokine storm; hyaluronan; hyaluronidase.

Figure 1. A schematic diagram of SARS-CoV-2 infection shows the involvement of HA synthase, HA storm, cytokine storm, endothelial and immune cells.

Figure 2. Possible inhibitory mechanisms of 4-methylumbelliferine (4MU) on HA synthesis. 1: 4MU acts as a competitive inhibitor of UGT (an enzyme required for transfer of UDP to glucuronic acid to form precursors of hyaluronan synthesis). 4MU acts in the initial step of HA synthesis by forming a covalent bond with the glucuronic acid, as a result, a substrate for HA synthase (UDP-glucuronic acid) is decreased leading to an inhibition of HA production). 2: 4MU decreases mRNA expression of HA synthase (an enzyme required for the late step of HA synthesis). However, the underlying mechanism of the decreased mRNA expression is still unclear.