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

doi:10.1172/jci.insight.150107

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 Jr

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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 language	English
Article number	150107
Number of pages	17
Journal	JCI Insight
Volume	6
Issue number	15
Early online date	29 Jun 2021
DOIs	https://doi.org/10.1172/jci.insight.150107
Publication status	Published - 9 Aug 2021

Bibliographical note

Funding Information: We wish to thank the families who provided consent for autopsy and the patients with COVID-19 who provided plasma samples. We thank Mike Solga, University of Virginia Flow Cytometry Core, for cytokine measurements, Ron Grider for electronic medical record data extraction, Panwichit Tongvichit for plasma sample collection, Patcharin Pramoonjago for Biomedical Tissue Repository support, Jennifer White for IRB protocol preparation, Sanford Feldman for comparative medicine support, Desiree Marshall and Stella Pearson for the support of the pathology specimens, Indika Mallawaarachchi and Arti Patel for N3C analyses, and Nicholas R. Natale and William A. Petri for technical support. SARS-CoV-2 Hong Kong/ VM20001061/2020 was obtained from BEI Resources. Funding: This work was supported by grants from the Manning Family Foundation, Ivy Foundation, Henske Family, and NIH R01 AI124214 (to WAP); by R01 AI148518 (to CM); by NIH R01 AI146257 (to SB); by NIH UL1TR003015/KL2TR003016 (to JMS); by the Department of Laboratory Medicine and Pathology, University of Washington (to BTB); by the Wellcome Trust 106898/A/15/Z, Wellcome Trust 203128/Z/16/Z and MRC-UK MR/K01207X/2 (to JEA); by the Asthma UK & Medical Research Foundation MRFAUK-2015-302, SP (to TES); by the German Research Foundation (DFG): PR1562/1-1, TRR295, and KFO339 (to SP and RP); and by NCATS U24 TR002306 and UVA UL1 TR003015 (to JJL and SJR). Portions of this work were also supported by the UVA School of Data Science and by NSF Career award MCB-1350957 (to CM).

Keywords

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

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© 2021, Donlan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/
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Cite this

Donlan, A. N., Sutherland, T. E., Marie, C., Preissner, S., Bradley, B. T., Carpenter, R. M., Sturek, J. M., Ma, J. Z., Moreau, G. B., Donowitz, J. R., Buck, G. A., Serrano, M. G., Burgess, S. L., Abhyankar, M. M., Mura, C., Bourne, P. E., Preissner, R., Young, M. K., Lyons, G. R., ... Jr, W. A. P. (2021). IL-13 is a driver of COVID-19 severity. JCI Insight, 6(15), Article 150107. https://doi.org/10.1172/jci.insight.150107

Donlan, AN, Sutherland, TE, Marie, C, Preissner, S, Bradley, BT, Carpenter, RM, Sturek, JM, Ma, JZ, Moreau, GB, Donowitz, JR, Buck, GA, Serrano, MG, Burgess, SL, Abhyankar, MM, Mura, C, Bourne, PE, Preissner, R, Young, MK, Lyons, GR, Loomba, JJ, Ratcliffe, SJ, Poulter, MD, Mathers, AJ, Day, AJ, Mann, BJ, Allen, JE & Jr, WAP 2021, 'IL-13 is a driver of COVID-19 severity', JCI Insight, vol. 6, no. 15, 150107. https://doi.org/10.1172/jci.insight.150107

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title = "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.",

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

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

note = "Funding Information: We wish to thank the families who provided consent for autopsy and the patients with COVID-19 who provided plasma samples. We thank Mike Solga, University of Virginia Flow Cytometry Core, for cytokine measurements, Ron Grider for electronic medical record data extraction, Panwichit Tongvichit for plasma sample collection, Patcharin Pramoonjago for Biomedical Tissue Repository support, Jennifer White for IRB protocol preparation, Sanford Feldman for comparative medicine support, Desiree Marshall and Stella Pearson for the support of the pathology specimens, Indika Mallawaarachchi and Arti Patel for N3C analyses, and Nicholas R. Natale and William A. Petri for technical support. SARS-CoV-2 Hong Kong/ VM20001061/2020 was obtained from BEI Resources. Funding: This work was supported by grants from the Manning Family Foundation, Ivy Foundation, Henske Family, and NIH R01 AI124214 (to WAP); by R01 AI148518 (to CM); by NIH R01 AI146257 (to SB); by NIH UL1TR003015/KL2TR003016 (to JMS); by the Department of Laboratory Medicine and Pathology, University of Washington (to BTB); by the Wellcome Trust 106898/A/15/Z, Wellcome Trust 203128/Z/16/Z and MRC-UK MR/K01207X/2 (to JEA); by the Asthma UK & Medical Research Foundation MRFAUK-2015-302, SP (to TES); by the German Research Foundation (DFG): PR1562/1-1, TRR295, and KFO339 (to SP and RP); and by NCATS U24 TR002306 and UVA UL1 TR003015 (to JJL and SJR). Portions of this work were also supported by the UVA School of Data Science and by NSF Career award MCB-1350957 (to CM). ",

year = "2021",

month = aug,

day = "9",

doi = "10.1172/jci.insight.150107",

language = "English",

volume = "6",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "15",

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TY - JOUR

T1 - IL-13 is a driver of COVID-19 severity

AU - Donlan, Alexandra N.

AU - Sutherland, Tara E.

AU - Marie, Chelsea

AU - Preissner, Saskia

AU - Bradley, Benjamin T.

AU - Carpenter, Rebecca M.

AU - Sturek, Jeffrey M.

AU - Ma, Jennie Z.

AU - Moreau, G. Brett

AU - Donowitz, Jeffrey R.

AU - Buck, Gregory A.

AU - Serrano, Myrna G.

AU - Burgess, Stacey L.

AU - Abhyankar, Mayuresh M.

AU - Mura, Cameron

AU - Bourne, Philip E.

AU - Preissner, Robert

AU - Young, Mary K.

AU - Lyons, Genevieve R.

AU - Loomba, Johanna J.

AU - Ratcliffe, Sarah J.

AU - Poulter, Melinda D.

AU - Mathers, Amy J.

AU - Day, Anthony J.

AU - Mann, Barbara J

AU - Allen, Judith E.

AU - Jr, William A. Petri

N1 - Funding Information: We wish to thank the families who provided consent for autopsy and the patients with COVID-19 who provided plasma samples. We thank Mike Solga, University of Virginia Flow Cytometry Core, for cytokine measurements, Ron Grider for electronic medical record data extraction, Panwichit Tongvichit for plasma sample collection, Patcharin Pramoonjago for Biomedical Tissue Repository support, Jennifer White for IRB protocol preparation, Sanford Feldman for comparative medicine support, Desiree Marshall and Stella Pearson for the support of the pathology specimens, Indika Mallawaarachchi and Arti Patel for N3C analyses, and Nicholas R. Natale and William A. Petri for technical support. SARS-CoV-2 Hong Kong/ VM20001061/2020 was obtained from BEI Resources. Funding: This work was supported by grants from the Manning Family Foundation, Ivy Foundation, Henske Family, and NIH R01 AI124214 (to WAP); by R01 AI148518 (to CM); by NIH R01 AI146257 (to SB); by NIH UL1TR003015/KL2TR003016 (to JMS); by the Department of Laboratory Medicine and Pathology, University of Washington (to BTB); by the Wellcome Trust 106898/A/15/Z, Wellcome Trust 203128/Z/16/Z and MRC-UK MR/K01207X/2 (to JEA); by the Asthma UK & Medical Research Foundation MRFAUK-2015-302, SP (to TES); by the German Research Foundation (DFG): PR1562/1-1, TRR295, and KFO339 (to SP and RP); and by NCATS U24 TR002306 and UVA UL1 TR003015 (to JJL and SJR). Portions of this work were also supported by the UVA School of Data Science and by NSF Career award MCB-1350957 (to CM).

PY - 2021/8/9

Y1 - 2021/8/9

N2 - 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.

AB - 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.

KW - Animals

KW - COVID-19/blood

KW - Disease Models

KW - Animal

KW - Disease Progression

KW - Female

KW - Humans

KW - Interleukin-13/blood

KW - Lung/immunology

KW - Male

KW - Mice

KW - Inbred C57BL

KW - SARS-CoV-2/immunology

KW - Severity of Illness Index

U2 - 10.1172/jci.insight.150107

DO - 10.1172/jci.insight.150107

M3 - Article

SN - 2379-3708

VL - 6

JO - JCI Insight

JF - JCI Insight

IS - 15

M1 - 150107

ER -

IL-13 is a driver of COVID-19 severity

Abstract

Bibliographical note

Keywords

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