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IL-13 Is a Driver of COVID-19 Severity

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IL-13 Is a Driver of COVID-19 Severity IL-13 is a driver of COVID-19 severity Alexandra N. Donlan, … , Judith E. Allen, William A. Petri Jr. JCI Insight. 2021. https://doi.org/10.1172/jci.insight.150107. Research In-Press Preview COVID-19 Immunology 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, 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 polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator. Finally, hyaluronan 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 hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases. Find the latest version: https://jci.me/150107/pdf 1 Title: IL-13 is a driver of COVID-19 severity 2 Authors: Alexandra N. Donlan1,2, *Tara E. Sutherland3, Chelsea Marie1, Saskia Preissner4, 3 Benjamin T. Bradley5, Rebecca M. Carpenter1, Jeffrey M. Sturek6, Jennie Z. Ma7, G. Brett 4 Moreau1, Jeffrey R. Donowitz1,8, Gregory A. Buck9, Myrna G. Serrano9, Stacey L. Burgess1, 5 Mayuresh M. Abhyankar1, Cameron Mura10, Philip E. Bourne10, Robert Preissner11, Mary K. 6 Young1, Genevieve R. Lyons7, Johanna J. Loomba12, Sarah J Ratcliffe7, Melinda D. Poulter13, 7 Amy J. Mathers1,13, Anthony J. Day3,14, *Barbara J. Mann1,2, *Judith E. Allen3,14, *William A. 8 Petri, Jr.1,2,13,# 9 10 Affiliations: 11 1Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of 12 Medicine, Charlottesville VA 22908 USA 13 2Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, 14 Charlottesville VA 22908 USA 15 3 Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, University of 16 Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, United Kingdom 17 4Department Oral and Maxillofacial Surgery, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, 18 Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany, 19 5Department of Laboratory Medicine and Pathology, University of Washington, Seattle WA 98109 USA 20 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia School of 21 Medicine, Charlottesville VA 22908 USA 22 7Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville VA 22908 USA, 23 8Division of Pediatric Infectious Diseases, Children’s Hospital of Richmond, Virginia Commonwealth University, 24 Richmond VA 23298 USA 25 9Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, 26 Richmond VA 23298 USA 27 1 1 10School of Data Science and Department of Biomedical Engineering University of Virginia, Charlottesville, VA 2 22904, 3 11Science-IT and Institute of Physiology, Charité – Universitätsmedizin Berlin, corporate member of Freie 4 Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Philippstrasse 12, 10115 Berlin, 5 Germany 6 12Integrated Translational Health Research Institute (iTHRIV), University of Virginia School of Medicine, 7 Charlottesville VA 22908 USA, 8 13Department of Pathology University of Virginia School of Medicine, Charlottesville VA 22908 USA, 9 14 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine 10 and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, United 11 Kingdom 12 13 *Co-senior authors 14 15 #To whom correspondence should be addressed: 16 Division of Infectious Diseases 17 University of Virginia School of Medicine 18 345 Crispell Drive, Charlottesville VA 22908-1340 USA 19 [email protected] 20 21 Competing interests: William A. Petri, Jr. receives research funding from Regeneron, Inc. 22 which is the maker of Dupilumab. The other authors declare no competing interests. 23 24 25 2 1 Abstract: Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 2 infection. Understanding the mechanisms by which the immune system contributes to COVID- 3 19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL- 4 13) was associated with the need for mechanical ventilation in two independent patient cohorts. 5 In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks 6 IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 7 neutralization reduced death and disease severity without affecting viral load, demonstrating an 8 immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, 9 hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the 10 hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan 11 was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced 12 mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator. 13 Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, 14 indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan 15 has important implications for therapy of COVID-19 and potentially other pulmonary diseases. 16 17 Summary: IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of 18 disease, IL-13 neutralization reduced disease and decreased lung hyaluronan deposition. 19 Administration of IL-13 induced hyaluronan in the lung. Blockade of the hyaluronan receptor 20 CD44 prevented mortality, highlighting a novel mechanism for IL-13-mediated hyaluronan 21 synthesis in pulmonary pathology. 22 3 1 Main Text: 2 SARS-CoV-2, the infectious agent causing the ongoing global COVID-19 pandemic, is a virus 3 that primarily infects the lower respiratory tract of hosts by gaining entry to cells via the receptor 4 angiotensin converting enzyme 2 (ACE2) facilitated by the transmembrane receptor neuropilin-1 5 (1, 2). The clinical course following infection varies widely from asymptomatic carriage to life- 6 threatening respiratory failure and death. 7 8 Since early in the pandemic, it was recognized that patients with severe forms of disease, e.g. 9 requiring hospitalization or ventilation, exhibited elevated levels of inflammatory cytokines (3). 10 This inflammatory state was associated with end-organ damage and in some cases death (4, 5). 11 While it remains unclear how the individual cytokines associated with this response may be 12 involved in severe outcomes in patients, inflammation is thought to be a primary driver of later 13 stages of this disease. In support of this hypothesis, the use of the anti-inflammatory steroid, 14 dexamethasone, decreased mortality by 29% in COVID-19 patients who required mechanical 15 ventilation (6). 16 17 Aligned with these clinical observations, efforts to characterize the host response to infection and 18 identify contributors to severe clinical outcomes have been ongoing since the pandemic began. 19 Proinflammatory mediators such as the cytokines interleukin-6 (IL-6) and TNF have been 20 associated with severe disease. Cytokine-targeted therapies have been proposed and in some 21 cases are in clinical trials. For example, the recently completed Adaptive COVID-19 Treatment 22 Trial 2 (ACTT-2) showed a faster time to recovery with remdesivir plus the Janus kinase 4 1 inhibitor baracitinib compared to remdesivir alone (7), as well as ACTT-4 which is comparing 2 baracitinib plus remdesivir vs dexamethasone plus remdesivir (8) 3 4 Descriptive studies of the immune response to SARS-CoV-2 have shown it to be highly 5 heterogeneous (9–11), including the observations that CD4+ T cells from COVID-19 patients 6 secreted the Th1 cytokine IFN-γ, the Th17 cytokines IL-17A and IL-17F, and the Th2 cytokine 7 IL-4 (12, 13). This level of diversity and variability make it especially challenging to find 8 specific drivers of disease and options for therapies. Consequently, understanding the 9 mechanisms by which distinct immune responses contribute to COVID-19 severity will be 10 crucial to designing personalized or targeted interventions, and ultimately to improve upon the 11 current steroid-based treatments. 12 13 In this study, we characterized the immune response of patients with COVID-19 and identified 14 the type 2 cytokine, IL-13 as associated with severe outcomes. Using a mouse model of COVID- 15 19, we discovered that IL-13 promotes severe disease, and that this response is likely to be at 16 least partially mediated by the deposition of hyaluronan in the lungs. 17 18 Results: 19 IL-13 is associated with severe COVID-19 in two patient cohorts 20 We analyzed plasma cytokines in 178 patients with COVID-19 at the University of Virginia 21 Hospital, 26 of whom received their care as outpatients and 152 as inpatients (Table S1A). 22 Cytokines were measured in the plasma sample taken closest to the first positive COVID-19 RT- 23 qPCR test (Figure S1). To understand the potential interrelationships between the different 5 1 cytokines measured in our cohort, we generated a heatmap for patients, grouped by 2 hospitalization and ventilation status (Figure 1A).
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