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A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase

Nature Medicine volume 6, pages 890–897 (2000)Cite this article

Abstract

Lymphocyte polyclonal activation is a generalized mechanism of immune evasion among pathogens. In a mouse model of Trypanosoma cruzi infection (American trypanosomiasis), reduced levels of polyclonal lymphocyte responses correlate with resistance to infection and cardiopathy. We report here the characterization of a parasite protein with B-cell mitogenic properties in culture supernatants of infective forms, the cloning of the corresponding gene and the analysis of the biological properties of its product. We characterized the protein as a co-factor-independent proline racemase, and show that its expression as a cytoplasmic and/or membrane-associated protein is life-stage specific. Inhibition studies indicate that availability of the racemase active site is necessary for mitogenic activity. This is the first report to our knowledge of a eukaryotic amino acid racemase gene. Our findings have potential consequences for the development of new immune therapies and drug design against pathogens.

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Figure 1: A 45-kDa B-cell polyclonal activator isolated from parasite culture supernatants.
Figure 2: Homology between the Tc45 protein and the bacterial proline racemases, and the genomic organization and transcription of the Tc45 gene.
Figure 3: Characterization of rTcPA45 mitogenic activity.
Figure 4: rTcPA45 is a proline racemase.
Figure 5: Differential expression of rTcPA45 protein in the parasite.
Figure 6: Correlation between mitogenic and racemase activities.

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Acknowledgements

We thank A. Waters, G. Langsley, J.C. Barale, S. Jarriault and L. de Mendonça Lima for discussions; P. Boussot and J. B. Boulé for help with automated sequencing and recombinant protein expression, respectively; L. Mulard for access to the polarimeter, A. Berneman for help with immunoblotting techniques; and E. Bischoff for helping with figure layouts. B.R.-S.-M. is a fellow of Consejo Nacional de Ciencia y Tecnologia #94587, México; W.D. is a fellow of the Pasteur/Fundação Oswaldo Cruz co-operative agreement and Institut National pour la Santé et la Techerche Médicale, France.

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Authors and Affiliations

  1. Département d'Immunologie, CNRS URA 1960, Institut Pasteur, 25 rue du Dr. Roux, Paris, 75724 CEDEX 15, France

    Bernardo Reina-San-Martín, Wim Degrave, Catherine Rougeot, Alain Cosson, Nathalie Chamond, Anabela Cordeiro-da-Silva & Paola Minoprio

  2. DBBM, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil 4365, Rio de Janeiro, 21045-900, Brazil

    Wim Degrave

  3. Département d'Immunologie, Unité de Biochimie et Génétique du Développement, CNRS URA 1960 Institut Pasteur, 25 rue du Dr. Roux, Paris, 75724 CEDEX 15, France

    Catherine Rougeot

  4. Instituto de Ciencias Biomédicas Abel Salazar, Universidade do Porto, Largo do Prof. Abel Salazar n °2, Porto, 4099, Portugal

    Anabela Cordeiro-da-Silva & Mario Arala-Chaves

  5. Instituto Gulbenkian de Ciência, CNRS 1961, rua da Quinta Grande n °6, apartado 14, Oeiras, 2782, Portugal

    Antonio Coutinho

  6. Unité d'Immunochimie Analytique Département d'Immunologie, Institut Pasteur, 25 rue du Dr. Roux, Paris, 75724 CEDEX 15, France

    Bernardo Reina-San-Martín, Wim Degrave, Alain Cosson, Nathalie Chamond & Paola Minoprio

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  1. Bernardo Reina-San-Martín
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Correspondence to Paola Minoprio.

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Reina-San-Martín, B., Degrave, W., Rougeot, C. et al. A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase. Nat Med 6, 890–897 (2000). https://doi.org/10.1038/78651

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