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Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism

Nature Immunology volume 2, pages 346–352 (2001)Cite this article

Abstract

Leptospira interrogans are zoonotic pathogens that have been linked to a recent increased incidence of morbidity and mortality in highly populated tropical urban centers. They are unique among invasive spirochetes in that they contain outer membrane lipopolysaccharide (LPS) as well as lipoproteins. Here we show that both these leptospiral outer membrane constituents activate macrophages through CD14 and the Toll-like receptor 2 (TLR2). Conversely, it seems that TLR4, a central component for recognition of Gram-negative LPS, is not involved in cellular responses to L. interrogans. We also show that for intact L. interrogans, it is LPS, not lipoprotein, that constitutes the predominant signaling component for macrophages through a TLR2 pathway. These data provide a basis for understanding the innate immune response caused by leptospirosis and demonstrate a new ligand specificity for TLR2.

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Figure 1: Gel mobility and protein profile of LPS preparations.
Figure 2: Activation of NF-κB by leptospiral LPS is CD14-dependent.
Figure 3: Cell stimulation by leptospiral LPS requires TLR2.
Figure 4: Activation of THP-1.hCD14 cells with leptospiral LPS and whole, heat-killed L. interrogans.
Figure 5: CD14 and TLR2 mediate activation of THP-1.hCD14 cells in response to leptospiral LPS or intact L. interrogans.
Figure 6: Activation of THP-1.hCD14 cells by whole B. burgdorferi is TLR2-dependent and unaffected by polymyxin B.
Figure 7: Activation of THP-1.hCD14 cells by LipL32 is CD14- and TLR2-dependent, abrogated by proteinase K, but unaffected by polymyxin B.
Figure 8: TLR2-deficient mice do not to respond to leptospiral LPS.

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Acknowledgements

Supported by grants AI-15136, GM-28485 and GM-37696 from the National Institutes of Health (to R. J. U.), a Beginning Grant-in-Aid from the American Heart Association Western States Affiliate (to R. I. T.) and by a postdoctoral fellowship from North Atlantic Treaty Organization (to C. W.).

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Author notes

  1. Catherine Werts and Richard I. Tapping: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, CA, USA

    Catherine Werts, Richard I. Tapping, John C. Mathison, Tsung-Hsien Chuang, Vladimir Kravchenko, Peter S. Tobias & Richard J. Ulevitch

  2. Unité de Bactériologie Moléculaire et Médicale, Institut Pasteur, 75724 Cedex 15, Paris, France

    Catherine Werts & Isabelle Saint Girons

  3. Division of Infectious Diseases, 111F, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, 90073, CA, USA

    David A. Haake

  4. Department of Molecular Biology, Genentech Inc., San Francisco, 94080, CA, USA

    Paul J. Godowski

  5. Department of Immunology, University of Washington, H-574 Health Sciences, Box 357650, Seattle, 98195, WA, USA

    Fumitaka Hayashi, Adrian Ozinsky, David M. Underhill & Alan Aderem

  6. Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstr. 4, Munich, D-81675, Germany

    Carsten J. Kirschning & Hermann Wagner

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Werts, C., Tapping, R., Mathison, J. et al. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat Immunol 2, 346–352 (2001). https://doi.org/10.1038/86354

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