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Targeting antitoxins to the intestine
Neutralizing antibodies against Clostridioides difficile toxins TcdA and TcdB have shown promise in combating intestinal C. difficile infection (CDI), but strategies to target such antibodies to the colon are lacking. Chen et al. generated a stable transfectant of Saccharomyces boulardii expressing neutralizing tetra-specific antibodies against these C. difficile toxins. Oral administration of the modified S. boulardii strain showed efficacy against primary and recurrent infection in prophylactic and therapeutic mouse models of CDI, indicating the potential of the engineered probiotic to treat this intestinal disease.
Abstract
Antibiotic-resistant Clostridioides difficile is an anaerobic Gram-positive bacterium that colonizes the colon and is responsible for more than 29,000 deaths in the United States each year. Hence, C. difficile infection (CDI) poses an urgent threat to public health. Antibody-mediated neutralization of TcdA and TcdB toxins, the major virulence factors of CDI, represents an effective strategy to combat the disease without invoking antibiotic resistance. However, current antitoxin approaches are mostly based on parenteral infusion of monoclonal antibodies that are costly, narrow spectrum, and not optimized against the intestinal disease. Here, we engineered probiotic Saccharomyces boulardii to constitutively secrete a single tetra-specific antibody that potently and broadly neutralized both toxins and demonstrated protection against primary and recurrent CDI in both prophylactic and therapeutic mouse models of disease. This yeast immunotherapy is orally administered, can be used concurrently with antibiotics, and may have potential as a prophylactic against CDI risk and as a therapeutic for patients with CDI.
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