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

Jessica L. Forbester, Emily A. Lees, David Goulding, Sally Forrest, Amy Yeung, Anneliese Speak, Simon Clare, Eve L. Coomber, Subhankar Mukhopadhyay, Judith Kraiczy, Fernanda Schreiber, Trevor D. Lawley, Robert Hancock, Holm H. Uhlig, Matthias Zilbauer, Fiona Powrie, Gordon Dougan

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish
Pages10118-10123
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number40
DOIs
Publication statusPublished - 2 Oct 2018

Keywords

  • Interleukin-22
  • Intestinal organoids
  • Salmonella

ASJC Scopus subject areas

  • General

Cite this

Forbester, Jessica L. ; Lees, Emily A. ; Goulding, David ; Forrest, Sally ; Yeung, Amy ; Speak, Anneliese ; Clare, Simon ; Coomber, Eve L. ; Mukhopadhyay, Subhankar ; Kraiczy, Judith ; Schreiber, Fernanda ; Lawley, Trevor D. ; Hancock, Robert ; Uhlig, Holm H. ; Zilbauer, Matthias ; Powrie, Fiona ; Dougan, Gordon. / Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 40. pp. 10118-10123.
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Forbester, JL, Lees, EA, Goulding, D, Forrest, S, Yeung, A, Speak, A, Clare, S, Coomber, EL, Mukhopadhyay, S, Kraiczy, J, Schreiber, F, Lawley, TD, Hancock, R, Uhlig, HH, Zilbauer, M, Powrie, F & Dougan, G 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, vol. 115, no. 40, pp. 10118-10123. https://doi.org/10.1073/pnas.1811866115

Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells. / Forbester, Jessica L.; Lees, Emily A.; Goulding, David; Forrest, Sally; Yeung, Amy; Speak, Anneliese; Clare, Simon; Coomber, Eve L.; Mukhopadhyay, Subhankar; Kraiczy, Judith; Schreiber, Fernanda; Lawley, Trevor D.; Hancock, Robert; Uhlig, Holm H.; Zilbauer, Matthias; Powrie, Fiona; Dougan, Gordon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 40, 02.10.2018, p. 10118-10123.

Research output: Contribution to journalArticle

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T1 - Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells

AU - Forbester, Jessica L.

AU - Lees, Emily A.

AU - Goulding, David

AU - Forrest, Sally

AU - Yeung, Amy

AU - Speak, Anneliese

AU - Clare, Simon

AU - Coomber, Eve L.

AU - Mukhopadhyay, Subhankar

AU - Kraiczy, Judith

AU - Schreiber, Fernanda

AU - Lawley, Trevor D.

AU - Hancock, Robert

AU - Uhlig, Holm H.

AU - Zilbauer, Matthias

AU - Powrie, Fiona

AU - Dougan, Gordon

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N2 - 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.

AB - 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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JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

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