Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity

Department of Immunology, Institut Pasteur, CNRS, URA1961, Paris 75724, France.
Molecular Microbiology (Impact Factor: 4.42). 11/2005; 58(1):46-60. DOI: 10.1111/j.1365-2958.2005.04808.x
Source: PubMed


Polyclonal lymphocyte activation is one of the major immunological disturbances observed after microbial infections and among the primary strategies used by the parasite Trypanosoma cruzi to avoid specific immune responses and ensure survival. T. cruzi is the insect-transmitted protozoan responsible for Chagas' disease, the third public health problem in Latin America. During infection of its mammalian host, the parasite secretes a proline racemase that contributes to parasite immune evasion by acting as a B-cell mitogen. This enzyme is the first described eukaryotic amino acid racemase and is encoded by two paralogous genes per parasite haploid genome, TcPRACA and TcPRACB that give rise, respectively, to secreted and intracellular protein isoforms. While TcPRACB encodes an intracellular enzyme, analysis of TcPRACA paralogue revealed putative signals allowing the generation of an additional, non-secreted isoform of proline racemase by an alternative trans-splicing mechanism. Here, we demonstrate that overexpression of TcPRAC leads to an increase in parasite differentiation into infective forms and in its subsequent penetration into host cells. Furthermore, a critical impairment of parasite viability was observed in functional knock-down parasites. These results strongly emphasize that TcPRAC is a potential target for drug design as well as for immunomodulation of parasite-induced B-cell polyclonal activation.

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    • "The T. cruzi proline racemase gene TcPRACA, an enzyme that interconverts free l-proline and d-proline enantiomers [55], is a very similar example: it can produce mRNAs coding for either secreted or cytoplasmic protein. The secreted form is only expressed in metacyclic and trypomastigote stages [53] [56] and acts as a B-cell mitogen that helps to shift the host immune response towards a non-specific response [55]. The cytoplasmic version may play a role in regulating metabolism in epimastigotes [53] [55]. "
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    • "Interestingly, intracellular forms (amastigotes and intracellular epimastigotes) fulfill their energy requirements mainly from metabolites other than glucose, especially proline [176]. As previously mentioned, this amino acid also participates in the differentiation process from T. cruzi epimastigote to trypomastigote in the insect vector [186] [187] [213] and in the differentiation of the intracellular epimastigote to the trypomastigote forms in the mammalian host, a process that occurs in the cytoplasm of infected mammalian host cells [188]. In addition, it is well established that adhesion to the host cell surface prior to invasion requires the parasite to expend energy [214]. "
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    • "Our present data substantiate earlier findings showing that proline racemase plays a role in both infectivity and differentiation of T. cruzi (Chamond et al. 2005 "
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    ABSTRACT: Proline racemase is an important enzyme of Trypanosoma cruzi and has been shown to be an effective mitogen for B cells, thus contributing to the parasite's immune evasion and persistence in the human host. Recombinant epimastigote parasites overexpressing TcPRAC genes coding for proline racemase present an augmented ability to differentiate into metacyclic infective forms and subsequently penetrate host-cells in vitro. Here we demonstrate that both anti T. cruzi proline racemase antibodies and the specific proline racemase inhibitor pyrrole-2-carboxylic acid significantly affect parasite infection of Vero cells in vitro. This inhibitor also hampers T. cruzi intracellular differentiation.
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