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 4

Antibody-deficient mice (anti-CD20 treated) lost IL-33–mediated protection from a second C. difficile infection.

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Antibody-deficient mice (anti-CD20 treated) lost IL-33–mediated protecti...
Anti-CD20 was administered to deplete B cells on days –7, 3, 18, 33, 48, and 63, and mice infected on day 0 and infected for the 2nd time on day 60 with C. difficile strain R20291. (A) Experimental design; (B) survival curve; (C) first infection weight loss; (D) first infection clinical scores; (E) reinfection weight loss; (F) reinfection clinical scores (G) epithelial damage scoring; (H) H&E stain. Scale bars: 118.7 μm (left) and 191.4 μm (right). (I) Toxin B–specific plasma IgG; (J) IgA; (K) cecal IgG; and (L) cecal IgA measured on day 10 after second infection. MLN and colon were harvested on day 10 after reinfection. Colonic (M and N) B cells (CD45+ CD3– CD19+); (O and P) TH2 cells (CD45+CD3+ CD4+ GATA3+); (Q and R) neutrophils; (S–U) Treg (CD45+CD3+ CD4+ FOXP3+), and TH17 (CD45+CD3+ CD4+ RORγt+) cells; and (V and W) MLN B cells. (B) Comparison made by log-rank test (n = 26 in both groups). (C–F) Comparison made by 2-tailed Student’s t-test (C and D n = 26, E and F n = 15). (G) Šídák’s multiple comparisons test was used. (I–M, P, Q, T, U, and V) A 2-tailed t test for normally distributed data and a Mann-Whitney test for nonnormally distributed data were used. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. The error bar indicates SEM.