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Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines

Nature Medicine volume 15, pages 1259–1265 (2009)Cite this article

Abstract

We report that infection of draining lymph nodes (DLNs) by Salmonella typhimurium results in the specific downregulation of the homeostatic chemokines CCL21 and CXCL13, which are essential for normal DLN organization and function. Our data reveal that the mechanism of this suppression is dependent on S. typhimurium LPS (sLPS). The decrease in CCL21 expression involves interaction between sLPS and CCL21-producing cells within DLNs, triggering a distinct Toll-like receptor 4 (TLR4)-mediated host signaling response. In this response, suppressor of cytokine signaling-3 (Socs3) is upregulated, which negatively regulates mothers against decapentaplegic homolog-3 (Smad3)-initiated production of CCL21. Disruption of lymph node architecture and cellular trafficking enhances S. typhimurium virulence and could represent a mechanism of immune suppression used by pathogens that primarily target lymphoid tissue.

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Figure 1: S. typhimurium alters cellular trafficking within DLNs.
Figure 2: LPS induces the specific downregulation CCL21 and CXCL13 during S. typhimurium infection.
Figure 3: Homeostatic chemokine suppression is dependent on TLR4 expression.
Figure 4: Socs3 and Smad3 modulate LPS-mediated CCL21 suppression.
Figure 5: Adaptive immune contributions to limiting S. typhimurium infection.
Figure 6: Model of S. typhimurium-induced suppression of homeostatic chemokines.

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Acknowledgements

We would like to thank M. Krangel, M. Gunn, M. Kuehn, Y. He and W. Zhang for their discussions and J. Wright for the use of equipment. Salmonella strains χ3761 and χ8573 were a gift from R. Curtiss (Arizona State University) and M. Kuehn (Duke University). S. typhimurium SL1344 was a gift from A. Aballay (Duke University), and E. coli J96 was a gift from S. Normark (Umea University). G. Li provided technical advice. Z. Swan, C. Kunder, G. Li and A. Bickell provided critical manuscript review. This work was supported by US National Institutes of Health grants R01 AI35678, R01 DK077159, R01 AI50021, R37 DK50814 and R21 AI056101.

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Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA

    Ashley L St John & Soman N Abraham

  2. Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

    Soman N Abraham

  3. Departments of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, North Carolina, USA

    Soman N Abraham

  4. Program in Emerging Infectious Diseases, Duke-National University of Singapore, Graduate Medical School, Singapore, USA

    Soman N Abraham

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  1. Ashley L St John
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All experiments were performed by A.L.S. Experiments were designed by A.L.S. and S.N.A.

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Correspondence to Soman N Abraham.

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Supplementary Figs. 1–13, Supplementary Table 1 and Supplementary Methods (PDF 892 kb)

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St John, A., Abraham, S. Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines. Nat Med 15, 1259–1265 (2009). https://doi.org/10.1038/nm.2036

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