Puumala orthohantavirus dysregulates hyaluronan metabolism in lung cells and correlates with disease severity and lung impairment

Hantaviruses are globally distributed rodent-borne viruses that cause human diseases. In Europe, the Puumala orthohantavirus (PUUV) is the most prevalent hantavirus and causes a mild form of hemorrhagic fever with renal syndrome (HFRS), characterized by renal, hemorrhagic and pulmonary manifestations. To date, the mechanisms underlying pulmonary symptoms are still poorly understood, highlighting a significant gap in our knowledge of the disease. In this translational study, we investigated the role of hyaluronan (HA), an extracellular matrix glycosaminoglycan with a high water-retaining capacity, in pulmonary disease severity during PUUV infection and examined whether PUUV disrupts HA metabolism. We found that plasma HA levels increased during acute PUUV infection, normalized during convalescence, and correlated with disease severity. In lung tissue from fatal PUUV cases, HA accumulated extensively and was associated with disrupted alveolar architecture. Furthermore, in bronchoalveolar lavage fluid, high-molecular weight HA levels were elevated in patients with greater pulmonary involvement. In vitro, infecting a panel of human lung cell types, we found that PUUV infection altered HA homeostasis in a cell-type-specific manner. Infection induced an imbalance in HA metabolic pathways, with early upregulation of hyaluronan synthases followed by induction of HA degradation and receptor genes. Primary lung fibroblasts similarly showed increased HA production with pronounced donor variability in HA regulating gene expression not explained by infection levels. These findings identify dysregulated HA metabolism as a feature of PUUV infection and link pulmonary HA accumulation to disease severity, implicating HA as a potential biomarker and therapeutic target in hantavirus associated lung disease.