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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI184659

IL33 protects from recurrent C. difficile infection by restoration of humoral immunity

Farha Naz,1 Md Jashim Uddin,1 Nicholas M. Hagspiel,1 Mary K. Young,1 David Tyus,1 Rachel Boone,2 Audrey C. Brown,1 Girija Ramakrishnan,1 Isaura Rigo,1 Claire Fleming,1 Gregory R. Madden,1 and William A. Petri Jr.1

1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

Find articles by Ramakrishnan, G. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

Find articles by Rigo, I. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

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1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

Find articles by Madden, G. in: JCI | PubMed | Google Scholar

1Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Chalottesville, United States of America

3Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Chalottesville, United States of America

Find articles by Petri Jr., W. in: JCI | PubMed | Google Scholar |

Published March 6, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI184659.
Copyright © 2025, Naz et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 6, 2025 - Version history
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Abstract

Clostridioides difficile infection (CDI) recurs in one of five patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL33 measured at diagnosis predicts future recurrence, leading us to test the role of IL33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL33 was demonstrated to be integral for anti-TcdB antibody production. IL33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL33 protection from reinfection was antibody-dependent, as mMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL33 in generating humoral immunity to prevent recurrent CDI.

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