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 1

IL-33 increases toxin-specific antibody in mice after first infection with C. difficile.

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IL-33 increases toxin-specific antibody in mice after first infection wi...
IL-33 (0.75 μg) was administered i.p. on days –4 to 0 to C57BL/6J mice (A–H) and/or ST2−/− mice (I–M). Mice were infected with C. difficile strain R20291 (A–E and G–M) or VPI 10463 (F). On day 15 after infection, antibodies were measured in plasma and cecal content. (A) Schematic diagram showing infection and treatment timeline; (B) survival curves; (C) weight loss; (D) clinical scores; (E) plasma toxin B–specific IgG from mice infected with C. difficile strain R20291; (F) plasma toxin B–specific IgG from mice infected with C. difficile strain VPI 10463; (G) plasma toxin B–specific IgM from mice infected with C. difficile strain R20291; (H) cecal content toxin B–specific IgA from mice infected with C. difficile strain R20291. (I–M) WT versus ST2−/− mice infected with C. difficile strain R20291: (I) Schematic diagram showing infection and treatment timeline; (J) plasma IgG; (K) cecal IgG; (L) cecal IgA; and (M) plasma IgM. (B) Comparison made by log-rank test (n = 30). (C and D) Comparison made by 2-tailed Student’s t test (C and D n = 30). E (n = 16), F (n = 11), G (n = 25), H (n = 18), J (n = 14), K (n = 7), L (n = 7), M (n = 7), 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, and ***P < 0.001. The error bar indicates SEM.