Alexandra N. Donlan 1 , 2 , Tara E. Sutherland 3 , Chelsea Marie 1 , Saskia Preissner 4 , Ben T. Bradley 5 , Rebecca M. Carpenter 1 , Jeffrey M. Sturek 6 , Jennie Z. Ma 7 , G. Brett Moreau 1 , Jeffrey R. Donowitz 1 , 8 , Gregory A. Buck 9 , Myrna G. Serrano 9 , Stacey L. Burgess 1 , Mayuresh M. Abhyankar 1 , Cameron Mura 10 , Philip E. Bourne 10 , Robert Preissner 11 , Mary K. Young 1 , Genevieve R. Lyons 7 , Johanna J. Loomba 12 , Sarah J Ratcliffe 7 , Melinda D. Poulter 13 , Amy J. Mathers 1 , 13 , Anthony Day 3 , 14 , Barbara J. Mann 1 , Judith E. Allen 3 , 14 , William A. Petri Jr. 1 , 2 , 13 , #
01 March 2021
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 interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab 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, in the lung, hyaluronan synthase 1 ( Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.
IL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronan’s receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.