IL-13 is a driver of COVID-19 severity

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Alexandra N Donlan
  • 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 Loomba
  • Sarah J Ratcliffe
  • Melinda D Poulter
  • Amy J Mathers
  • Barbara J Mann
  • William A Petri

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.

Bibliographical metadata

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