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.
【저자키워드】 COVID-19, immunology, Cytokines, Innate immunity, Th2 response, 【초록키워드】 Treatment, therapy, Mortality, severe COVID-19, mechanical ventilation, neutralization, SARS-COV-2 infection, disease severity, COVID-19 severity, lung, Lung disease, cytokine, immune system, Viral, Viral load, mice, Lungs, Patient, death, understanding, plasma, receptor, polysaccharide, characteristic, mouse model, mechanism, mAb, IL-13, IL-4, Signaling, administration, pulmonary diseases, severe disease, immune dysregulation, Dupilumab, Pulmonary pathology, Hyaluronan, dysregulation, open, mediator, accumulation, Stage, SARS-CoV-2–infected mice, pathogenic, blockade, patient cohorts, CD44, Has1, block, implication, independent, addition, the disease, elevated, reduced, less, contribute, prevented, without affecting, highlighting, downregulated gene, patients with COVID-19, was increased,