Monoclonal anti-toxin therapy supports the protective innate immune response following Clostridioides difficile infection

Abstract Clostridioides difficile causes over 200,000 hospitalizations and 13,000 deaths annually in the United States. C. difficile infects the large intestine following perturbation of the microbiome to cause pathology that ranges in severity from diarrhea to pseudomembranous colitis. Virulence factors Toxin A and Toxin B are the primarily drivers of disease. These toxins damage the epithelial barrier leading to pathologic inflammation and bacterial translocation. Monoclonal antibodies (mAbs) that neutralize Toxin A and Toxin B, actoxumab and bezlotoxumab, respectively, significantly reduce disease severity in a murine model of C. difficile infection, however the impact of toxin neutralization on the induction of the innate immune response following infection is unknown. The goal of this study was to define the quality of the host innate immune response in the context of anti-toxin mAb therapy. At day 2 post-infection, C. difficile infected, mAb-treated mice had significantly less disease despite no differences in C. difficile burden compared to isotype-treated mice. Further, no difference in neutrophil infiltration or production of IFNg or IL-17 from innate lymphoid cells (ILCs) was observed within the intestinal lamina propria following infection. However, C. difficile-infected, mAb-treated mice had increased IL-22-producing ILCs and increased eosinophil infiltration in the intestine compared to iso-treated mice. Both IL-22 +ILCs and eosinophils promote protective host response following C. difficile infection. These findings indicate that activation of natural host protective mechanisms remain intact in the context of treatment that neutralizes toxin but does not alter C. difficile burden in the intestine. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA