Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells.
Forbester, Jessica L
Lees, Emily A
Coomber, Eve L
Lawley, Trevor D
Hancock, Robert EW
Uhlig, Holm H
Proceedings of the National Academy of Sciences of the United States of America
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Forbester, J. L., Lees, E. A., Goulding, D., Forrest, S., Yeung, A., Speak, A., Clare, S., et al. (2018). Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells.. Proceedings of the National Academy of Sciences of the United States of America, 115 (40), 10118-10123. https://doi.org/10.1073/pnas.1811866115
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.
Intestinal Mucosa, Phagosomes, Epithelial Cells, Humans, Salmonella typhimurium, Salmonella Infections, Interleukins, Interleukin-10 Receptor beta Subunit, Interleukin-21 Receptor alpha Subunit, Induced Pluripotent Stem Cells
External DOI: https://doi.org/10.1073/pnas.1811866115
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289487
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/