IL-33 protects from recurrent C. difficile infection by restoration of humoral immunity
Farha Naz, Md Jashim Uddin, Nicholas Hagspiel, Mary K. Young, David Tyus, Rachel Boone, Audrey C. Brown, Girija Ramakrishnan, Isaura Rigo, Claire Fleming, Gregory R. Madden, William A. Petri Jr.
Farha Naz, Md Jashim Uddin, Nicholas Hagspiel, Mary K. Young, David Tyus, Rachel Boone, Audrey C. Brown, Girija Ramakrishnan, Isaura Rigo, Claire Fleming, Gregory R. Madden, William A. Petri Jr.
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Research Article Immunology Infectious disease

IL-33 protects from recurrent C. difficile infection by restoration of humoral immunity

Abstract

Clostridioides difficile infection (CDI) recurs in 1 of 5 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 IL-33 measured at diagnosis predicts future recurrence, leading us to test the role of IL-33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL-33 was demonstrated to be integral for anti-TcdB antibody production. IL-33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL-33 protection from reinfection was antibody-dependent, as μMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL-33 in generating humoral immunity to prevent recurrent CDI.

Authors

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

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Figure 3

IL-33 protection from a second C. difficile infection is antibody dependent.

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IL-33 protection from a second C. difficile infection is antibody depend...
WT (n = 15) and μMT-KO (n = 15) mice were administered IL-33 (0.75 μg) i.p. on days –4 to 0 and mice infected on day 0 and reinfected on day 60 with C. difficile strain R20291. (A) Experimental design; (B) first infection weight loss; (C) clinical scores. WT and μMT-KO mice were reinfected with C. difficile R20291 60 days after the first infection. Reinfection (D) weight loss; (E) Stool C. difficile toxin A and B measured by ELISA kit (Techlab); (F) FITC-dextran gut permeability assay; (G) H&E stain; (H) epithelial damage scoring. Scale bars: 267.3 μm (left) and 231.2 μm (right). (B–D) Comparison made by 2-tailed Student’s t test (D n=18). (E) a 2-tailed t test was used and the error bar indicates SEM. (F) a Mann-Whitney test was used and the error bar indicates the median with interquartile range. (H) Šídák’s multiple comparisons test was used. *P < 0.05, **P < 0.01, and ***P < 0.001.