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Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

Nature Medicine volume 14, pages 421–428 (2008)Cite this article

Abstract

Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (TH17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by TH17 responses, including the expression of interleukin-17 (IL-17) and IL-22. TH17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted TH17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor–deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract.

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Figure 1: Gene expression profiling of the host response to S. typhimurium infection.
Figure 2: Cytokine expression elicited by S. typhimurium in SIV-infected (n = 4) and SIV-negative control macaques (n = 4) 5 h after infection.
Figure 3: Kinetics of lymphocyte depletion and viral replication in SIV-infected macaques compared to naive controls.
Figure 4: Analysis of lamina propria T lymphocytes.
Figure 5: Bacterial translocation from the intestinal mucosa to internal organs in rhesus macaques and mice.
Figure 6: Host responses elicited 48 h after S. typhimurium infection in the cecal mucosa of C57BL/6 mice or Il17ra−/− mice.

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Acknowledgements

We would like to thank C. Bevins and R. Tsolis for helpful suggestions to improve the manuscript. We would like to thank E. Reay and L. Hirst for their invaluable help in coordinating the macaque studies and Taconic Corporation for providing Il17ra−/− mice for this study.

Work in A.J.B.'s laboratory was supported by US Public Health Service grants AI040124, AI044170 and AI065534. Work in S.D.'s laboratory was supported by US Public Health Service grants DK43183, DK61297 and AI43274. T.A.P. and R.L.S. were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil. R.L.S. was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil. I.G. was supported by Public Health Service grant AI06055.

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Author notes

  1. Manuela Raffatellu and Renato L Santos: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, 95616-8645, California, USA

    Manuela Raffatellu, Renato L Santos, David E Verhoeven, Michael D George, R Paul Wilson, Sebastian E Winter, Ivan Godinez, Sumathi Sankaran, Tatiane A Paixao, Satya Dandekar & Andreas J Bäumler

  2. Division of Gastroenterology, Faculty of Medicine, University of Liverpool, First Floor Nuffield Building, Ashton Street, Liverpool, L69 3BX, UK

    Melita A Gordon

  3. Children's Hospital of Pittsburgh, Suite 3765, 3705 Fifth Avenue, Pittsburgh, 15213, Pennsylvania, USA

    Jay K Kolls

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Correspondence to Andreas J Bäumler.

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Raffatellu, M., Santos, R., Verhoeven, D. et al. Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14, 421–428 (2008). https://doi.org/10.1038/nm1743

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