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Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells

Nature Immunology volume 4, pages 485–490 (2003)Cite this article

Abstract

Toxoplasma gondii releases factors that potently stimulate production of interleukin-12 (IL-12) from dendritic cells (DCs). Purification of this activity showed that cyclophilin-18 (C-18) was its principal component, and antibodies generated against recombinant C-18 inhibited tachyzoite extract–induced synthesis of IL-12. Recombinant C-18 showed high affinity for and triggered cell signaling through CCR5, a chemokine receptor important in parasite-induced IL-12 production by DCs. These findings suggest that the unusual potency of T. gondii in inducing IL-12 from DCs results from its synthesis of a unique chemokine mimic that signals through CCR5. The ability to generate this strong protective response may benefit parasite transmission by preventing the protozoan from overwhelming its intermediate hosts.

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Figure 1: Purification of the IL-12–inducing activity in culture supernatants of T. gondii tachyzoites.
Figure 2: Secretion of C-18 by isolated tachyzoites.
Figure 3: Induction of IL-12 by recombinant C-18.
Figure 4: Addition of C-18 enhances STAg-induced IL-12 production.
Figure 5: T. gondii cyclophilin binds to CCR5.
Figure 6: C-18 triggers Ca2+ flux and induces DC chemotaxis in a CCR5-dependent manner.
Figure 7: CsA inhibits IL-12–induction in vitro and in vivo by both STAg and recombinant T. gondii cyclophilin.

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Acknowledgements

We thank P. Murphy, E. Berger and H. Golding for suggestions and critical reading of this manuscript.

Author information

Author notes

  1. Hugues Charest

    Present address: Institut National de Santé Publique du Québec, Quebec, QC, Canada

  2. Julio Aliberti and Jesus G. Valenzuela: These authors contributed equally to this work.

Authors and Affiliations

  1. Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA

    Julio Aliberti, Sara Hieny, Hugues Charest & Alan Sher

  2. Medical Entomology Section, Laboratory of Malaria and Vector Research,

    Jesus G. Valenzuela, John Andersen & Jose M. Ribeiro

  3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA

    Jesus G. Valenzuela, John Andersen & Jose M. Ribeiro

  4. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, MD, USA

    Vern B. Carruthers

  5. Cancer Research UK, London Research Institute, London, WC2A 3PX, UK

    Caetano Reis e Sousa

  6. Department of Biochemistry, Wellcome Trust Building, University of Dundee, Dundee, DD1 5EH, Scotland, UK

    Alan Fairlamb

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Correspondence to Julio Aliberti.

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Supplementary information

Supplementary Fig. 1.

Specificity control for antiserum to C-18. Recombinant C-18 molecule (C), STAg (ST) and the tachyzoite culture supernatant (SN) (1μg/lane) were separated by denaturing gel electrophoresis (4-20% gel) and subsequently transferred to PVDF membranes. The figure shows an immunoblot, using for detection rabbit antisera anti-C-18 (1499) or normal rabbit serum (NRS) at a 1:5,000 dilution. (PDF 669 kb)

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Aliberti, J., Valenzuela, J., Carruthers, V. et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 4, 485–490 (2003). https://doi.org/10.1038/ni915

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