(460) Innate immune response to Vibrio cholerae in infant mouse model

Introduction/Rationale: Vibrio cholerae, the cholera pathogen, infects several million people and causes tens of thousands of deaths annually. V. cholerae is a curved, highly motile Gram-negative rod that associates with the epithelium of the human small intestine (SI), the site of colonization.
Knowledge of adaptive immune responses to natural and experimental V. cholerae infection in humans has expanded in recent years. Infection triggers protective antibody responses that can limit intestinal colonization and diarrhea. However, despite more than a century of studies on cholera pathogenesis, the understanding of innate immune responses to V. cholerae in the small intestine remains limited. In cholera naïve individuals, such responses are likely to be a critical determinant of survival, given that severe cholera can kill infected individuals within a day of infection before adaptive immune responses are generated.

Methods: Single-cell RNA-sequence was performed to characterize epithelial and immune cell response in Infant mice infected with V. cholerae

Results: V. cholerae infection increased the expression of IL22 in type 3 innate lymphoid cells and increased the abundance of an enterocyte subset specialized for defense. IL22-Fc fusion protein administration protects infant mice from diarrhea and death by V. cholerae infection. Mechanistically, IL22-Fc promotes the differentiation of epithelial stem cells into mucus-secreting goblet cells. Secretory mucus impaired V. cholerae's association with the epithelium.

Conclusion: These observations define mucosal responses to the cholera pathogen and suggest that stimulating the intestinal IL-22 pathway represents a host-directed approach for cholera therapy.