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. Loomba, Sarah J. Ratcliffe, Melinda D. Poulter, Amy J. Mathers, Anthony J. Day, Barbara J. Mann, Judith E. Allen, William A. Petri Jr.
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. Loomba, Sarah J. Ratcliffe, Melinda D. Poulter, Amy J. Mathers, Anthony J. Day, Barbara J. Mann, Judith E. Allen, William A. Petri Jr.
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Research Article COVID-19 Immunology

IL-13 is a driver of COVID-19 severity

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.

Authors

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. Loomba, Sarah J. Ratcliffe, Melinda D. Poulter, Amy J. Mathers, Anthony J. Day, Barbara J. Mann, Judith E. Allen, William A. Petri Jr.

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Figure 4

HA and COVID-19 disease.

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HA and COVID-19 disease. Mice received i.p. injections of anti–IL-13 on ...
Mice received i.p. injections of anti–IL-13 on days 0 and 2 after infection, were euthanized on day 5, and lung tissue was split and placed either into trizol tissue reagent for RNA analysis or formaldehyde for paraffin embedding and IHC. (A) Gene expression in mouse lung of Has1, the HA receptor Cd44, and Hyaluronidase 2 (Has2) of infected mice with anti–IL-13, isotype control antibody and uninfected controls (Tukey’s HSD). (B) Staining of HA in mouse lung (with HABP); Scale bar: 70μm. Rectangle indicates area magnified in image to left; Scale bar: 20μm. (C) Quantification of HA deposition in tissue following infection and neutralization of IL-13 (mixed effect model; combined 2 experiments). (D) Hyaluronan was measured in the plasma of COVID-19–negative controls and in patients with COVID-19 that did or did not require supplemental oxygen. Postmortem lung samples were obtained from fatal COVID-19 cases and control tissue from COVID-19 negative deaths. (E) Quantification of HA deposition in fatal COVID-19 disease (n = 11) and controls (n = 8) (log-transformed, mixed effect model) using HABP. (F) Representative images of staining for HA (with HABP) from human lung samples; Scale bar: 70μm. Rectangle indicates area magnified in image below; Scale bar: 20μm. Mice were administered anti-CD44 or IgG2 isotype control on each of day 1–4 after infection. (G) Kaplan-Meier survival curve (log-rank) and (H) Clinical scores for mice (Student’s t test); combined 2 independent experiments. Hyaluronan-binding protein, HABP. n = 5 mice/group. *P < 0.05; **P < 0.005; ***P < 0.0005.