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Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells

J. Forbester,E. Lees,D. Goulding,S. Forrest,Amy T. Y. Yeung,A. Speak,S. Clare,Eve L. Coomber,S. Mukhopadhyay,Judith Kraiczy,F. Schreiber,T. Lawley,R. Hancock,H. Uhlig,M. Zilbauer,F. Powrie,G. Dougan

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance We generated intestinal organoids from stem cells from a patient with infantile inflammatory bowel disease harboring a homozygous loss-of-function variant in the IL10RB gene, leaving the patient’s cells unable to respond to interleukin-22. Using both human stem cell and murine models, we show that IL-22 primes intestinal epithelial cells to control Salmonella infection more efficiently and that this control is abated in the patient organoids. This control is restored by introduction of a functional copy of the IL10RB gene into the patient’s cells. This work demonstrates the utility of stem cell-derived intestinal organoids as a tool for studying the effect of defined mutations on pathogen control, showing that organoids can provide an invaluable resource for pathogenesis research. Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22–induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22–pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.

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