SARS-CoV-2 infection induces hyaluronan production in vitro and hyaluronan levels in COVID-19 patients relate to morbidity and long-term lung impairment : a prospective cohort study

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. 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. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.IMPORTANCEThis study provides insights into the role of hyaluronan (HA) in the severity and long-term impact of COVID-19 on lung function. Through extensive morphological examination of lung tissues and a multicenter study, we identified that HA levels are significantly elevated in COVID
This study was supported by the Swedish Heart-Lung Foundation (20200385 to A.K.Ö. and A. Lenman, 20200325 and 20210078 to C.A., and 20200366 and 20210049 to A.B.), SciLife Lab COVID-19 research program funded by the Knut and Alice Wallenberg Foundation (2020.0182 and C19R:028 to A.K.Ö. and A. Lenman, and VC-2020-0015 to C.A.), Kempestiftelserna (grant no. JCK-1827 to A.K.Ö.), Umeå University and County Council of Västerbotten (#RV-938855 to C.A. and #RV-970074 to A.K.Ö.), Carl Bennet AB (A. Lenman), the Fundraising Foundation for Medical Research, Umeå University (978018 to A. Lenman and 964781 to U.H.), Nyckelfonden Örebro (OLL-938628 and OLL-961416 to S.C.) Regional Research Council Mid Sweden (RFR-968856 and RFR-940474 to S.C.), the Swedish Research Council (2020-06235 to M.N.E.F., 2016-06514 to J.N., and 2021-06602 to J.H.), Åke Wiberg’s foundation (M22-0106 to A. Lenman), Emil and Wera Cornell’s foundation (A. Lenman), and Magnus Bergvall's foundation (2022-186 to A. Lenman).