IL-13 is a driver of COVID-19 severity

Donlan, Alexandra N.; Sutherland, Tara E.; Marie, Chelsea; Preissner, Saskia; Bradley, Benjamin T.; Carpenter, Rebecca M.; Sturek, Jeffrey M.; Ma, Jennie Z.; Moreau, G. Brett; Donowitz, Jeffrey R.; Buck, Gregory A.; Serrano, Myrna G.; Burgess, Stacey L.; Abhyankar, Mayuresh M.; Mura, Cameron; Bourne, Philip E.; Preissner, Robert; Young, Mary K.; Lyons, Genevieve R.; Loomba, Johanna J.; Ratcliffe, Sarah J.; Poulter, Melinda D.; Mathers, Amy J.; Day, Anthony J.; Mann, Barbara J.; Allen, Judith E.; Petri, William A.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology.