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

Abstract

Rationale: High levels of hyaluronan in lungs and blood associate with COVID-19 severity. However, the effects on systemic hyaluronan concentrations and the mechanisms involved in the pathological overproduction of hyaluronan upon SARS-CoV-2 infection remain incompletely characterized. Objectives: To determine how hyaluronan levels in blood of COVID-19 patients change over time and investigate SARS-CoV-2 impact on hyaluronan metabolism along with the effect of corticosteroid treatment. Methods: The concentrations of hyaluronan were measured in blood plasma from patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS 6-9), both during the acute and convalescent phases. Primary human bronchial epithelial cells isolated from healthy donors were differentiated into an in vitro 3D-lung model and used to study effects of SARS-CoV-2 infection and corticosteroids treatment on hyaluronan metabolism. Measurements and Main results: Compared to healthy controls, both patients with mild and severe COVID-19 showed elevated plasma hyaluronan concentrations, which increased with disease severity. A reduction was observed over time, but hyaluronan levels remained elevated for at least 12 weeks, especially in women. SARS-CoV-2 infection in the 3D-lung model showed upregulation of inflammatory genes, hyaluronan synthases and downregulation of hyaluronidases, which increased the overall hyaluronan concentration. Notably, several of these effects were counteracted by corticosteroid treatment. Conclusions: Overproduction of hyaluronan plays a role in the pathogenesis of COVID-19 and hyaluronan levels in blood remain elevated over time. The in vitro mechanism for the positive effects of corticosteroid treatment in COVID-19 suggests a combined action of reduced inflammation and counteraction of hyaluronan synthesis.