Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. Then we briefly summarize the known roles of HA in airway inflammation and immunity. We then address what is known about HA and the pathogenesis of COVID-19 acute respiratory distress syndrome (COVID-19 ARDS). Next, we examine potential roles for HA in post-acute SARS-CoV-2 infection (PASC), also known as "long COVID" as well as in COVID-associated fibrosis. Finally, we discuss the potential therapeutics that target HA as a means to treat COVID-19, including the repurposed drug hymecromone (4-methylumbelliferone). We conclude that HA is a promising potential therapeutic target for the treatment of COVID-19.

Keywords: ARDS; COVID-19; Hyaluronan; Inflammation; PASC; SARS-CoV-2.

Fig. 1

A model for HA production in the COID-19 infected lung. A. HA production by airway cells in response to viral triggers. Inflammatory cytokines and viral PAMPs, including dsRNA, trigger HA production by respiratory epithelial cells. This HA production is mediated by HA synthases, most notably HAS2. The accumulation of HA fragments may perpetuate the inflammatory casecade associated with infection. B. While dying cells infected with SARS-CoV-2 make minimal HA, infection drives robust HA production by respiratory epithelial cells. This, together with DNA released from dead cells, results in thick, tenacious airway secretions in COVID-19 acute lung infections.

Fig. 2

A model for how HA might contribute to PASC pathophysiology. Thick, HA-rich hyaline material fills lung alveolae in response to acute SARS-CoV-2 infection. In severe acute COVID-19 infection, this can lead to thick respiratoty secretions, edema, and impaired gas exchange typical of ARDS. This HA is catabolized over time into LMW-HA, which drives further inflammation. Most individuals clear this HA via hyaladherin-mediated cellular uptake. However, when hyaladherin levels or function are impaired, HA persists and promotes fibrosis and poor gas exchange (respiratory PACS).