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Lysophospholipid sensing triggers secretion of flagellin from pathogenic salmonella

Nature Immunology volume 7, pages 583–589 (2006)Cite this article

Abstract

Flagellin induces inflammatory and innate immune responses through activation of Toll-like receptor 5. Here we show that proinflammatory monomeric flagellin produced by salmonella during infection of intestinal epithelial cells was not derived from polymeric bacterial cell wall–associated flagellum but instead was synthesized and secreted de novo by the bacterium after direct sensing of host-produced lysophospholipids. Inhibition of lysophospholipid biosynthesis in intestinal epithelial cells reduced flagellin production and release from salmonella. Lysophospholipids induced a cAMP-dependent signaling pathway in salmonella that resulted in production and secretion of active flagellin. The induction of Toll-like receptor ligand synthesis and secretion by a host signal represents a previously unknown regulatory mechanism for inflammation and innate immunity during infection with a bacterial pathogen.

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Figure 1: Contact with IECs activates release of proinflammatory flagellin from pathogenic salmonella.
Figure 2: The host stimulus that induces flagellin release from salmonella is not proteinaceous.
Figure 3: Lysophospholipids trigger secretion of flagellin from salmonella.
Figure 4: Lysophospholipids are the active components of the Caco-2-mediated release of flagellin from S. typhi.
Figure 5: Inhibition of iPLA2 ex vivo or in vivo reduces the ability C57BL/6 intestinal cells to trigger flagellin from S. typhimurium.
Figure 6: De novo expression of flagellin stimulated by host lysophospholipids.
Figure 7: Secretion of flagellin after activation of salmonella with LPC is regulated by cAMP.

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Acknowledgements

We thank S.K. Basu and S. Rath, R. Pal and D. Sehgal for critical reading of the manuscript; R.A. Vishwakarma for suggestions during lipid analysis; and A. Sakya for help with mass spectrometry. Supported by the Department of Biotechnology of the Government of India (to the National Institute of Immunology) and the Council of Scientific and Industrial Research of India (N.S.).

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  1. Hybridoma Laboratory, National Institute of Immunology, New Delhi, 110 067, India

    Naeha Subramanian & Ayub Qadri

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  1. Naeha Subramanian
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Correspondence to Ayub Qadri.

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Supplementary information

Supplementary Fig. 1

IL-8 secretion from Caco-2 cells in response to infection with S. typhi requires metabolically active bacteria. (PDF 95 kb)

Supplementary Fig. 2

S. typhimurium membrane inhibits LPA-induced release of flagellin from S. typhi. (PDF 64 kb)

Supplementary Fig. 3

Identification of LPC in Caco-2 culture supernatant by mass spectrometric analysis. (PDF 114 kb)

Supplementary Fig. 4

LPC does not cause shearing of S. typhi flagella. (PDF 52 kb)

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Subramanian, N., Qadri, A. Lysophospholipid sensing triggers secretion of flagellin from pathogenic salmonella. Nat Immunol 7, 583–589 (2006). https://doi.org/10.1038/ni1336

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