Hyaluronan in COVID-19 morbidity, a bedside-to-bench approach to understand mechanisms and long-term consequences of hyaluronan

Background We have previously shown that lungs from deceased COVID-19 patients are filled with hyaluronan (HA). In this translational study, we investigated the role of HA in all stages of COVID-19 disease, to map the consequences of elevated HA in morbidity and identify the mechanism of SARS-CoV-2-induced HA production. Methods Lung morphology was visualized in 3D using light-sheet fluorescence microscopy. HA was verified by immunohistochemistry, and fragmentation was determined by gas-phase electrophoretic molecular mobility analysis. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS 6-9), during the acute and convalescent phases and related to lung function. In vitro 3D-lung models differentiated from primary human bronchial epithelial cells were used to study effects of SARS-CoV-2 infection on HA metabolism. Findings Lungs of deceased COVID-19 patients displayed reduced alveolar surface area compared to healthy controls. We verified HA in alveoli and showed high levels of fragmented HA both in lung tissue and aspirates. Systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence and associated with reduced diffusion capacity. Transcriptomic analysis of SARS-CoV-2-infected lung models showed dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Corticosteroid treatment reduced inflammation and, also, downregulated HA synthases. Interpretation We show that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment. SARS-CoV-2 infection triggers a dysregulation of HA production, leading to increased concentrations of HA that are partially counteracted by corticosteroid treatment. Treatments directly targeting HA production and/or degradation can likely be used early during infection and may alleviate disease progression and prevent long-term lung complications.