IL-13 is a driver of COVID-19 severity

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

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Abstract

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.

Original languageEnglish
Article numbere150107
JournalJCI Insight
Volume6
Issue number15
DOIs
Publication statusPublished - 9 Aug 2021

Keywords

  • Animals
  • COVID-19/blood
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Interleukin-13/blood
  • Lung/immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • SARS-CoV-2/immunology
  • Severity of Illness Index

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