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Modulation of cardiocyte functional activity by antibodies against trypanosoma cruzi ribosomal P2 protein C terminus.

ABSTRACT: Antibodies against the Trypanosoma cruzi ribosomal P2beta protein (TcP2beta) have been associated with the chronic cardiac pathology of Chagas' disease in humans. Using synthetic peptides spanning the entire TcP2beta molecule, we investigated their epitope recognition by antibodies from mice chronically infected with T. cruzi and from mice immunized with two recombinant TcP2betas. We found clear differences in epitope recognition between antibodies from T. cruzi-infected mice and mice immunized with two different recombinant TcP2betas associated with different schedules of immunization. Major epitopes recognized by antibodies from mice immunized with recombinant glutathione S-transferase (GST) or histidine (Hist) fusion TcP2beta (GST-TcP2beta or Hist-TcP2beta) are located in the central and hinge regions of the molecule. Nevertheless, mice immunized with Hist-TcP2beta were also able to elicit antibodies against the TcP2beta C terminus, a region which is highly conserved in both T. cruzi and mammal ribosomal P proteins. Strikingly, antibodies from infected animals recognized only the TcP2beta C terminus. By using these antisera with distinct profiles of epitope recognition, it could be shown that only C terminus-specific antibodies were able to increase the beating frequency of cardiomyocytes from neonatal rats in vitro by selective stimulation of the beta1-adrenergic receptor. Thus, antibodies against the TcP2beta C terminus elicited in the absence of infection are able to modulate a functional activity of host cells through a molecular mimicry mechanism.

SUBMITTER: Sepulveda P

PROVIDER: S-EPMC101752 | biostudies-literature | 2000 Sep

REPOSITORIES: biostudies-literature

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Modulation of cardiocyte functional activity by antibodies against trypanosoma cruzi ribosomal P2 protein C terminus.

Sepulveda P P Liegeard P P Wallukat G G Levin M J MJ Hontebeyrie M M

Infection and immunity 20000901 9

Antibodies against the Trypanosoma cruzi ribosomal P2beta protein (TcP2beta) have been associated with the chronic cardiac pathology of Chagas' disease in humans. Using synthetic peptides spanning the entire TcP2beta molecule, we investigated their epitope recognition by antibodies from mice chronically infected with T. cruzi and from mice immunized with two recombinant TcP2betas. We found clear differences in epitope recognition between antibodies from T. cruzi-infected mice and mice immunized ...[more]

PMID: 10948133

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Project description:Several antigens from Trypanosoma cruzi, the causative agent of Chagas disease (CD), contain amino acid repeats identified as targets of the host immune response. Ribosomal proteins containing an Ala, Lys, Pro-rich repeat domain are among the T. cruzi antigens that are strongly recognized by antibodies from CD patients. Here we investigated the role of amino acid repeats present in the T. cruzi ribosomal protein L7a, by immunizing mice with recombinant versions of the full-length protein (TcRpL7a), as well as with truncated versions containing only the repetitive (TcRpL7aRep) or the non-repetitive domains (TcRpL7aΔRep). Mice immunized with full-length TcRpL7a produced high levels of IgG antibodies against the complete protein as well as against the repeat domain, whereas mice immunized with TcRpL7aΔRep or TcRpL7aRep produced very low levels or did not produce IgG antibodies against this antigen. Also in contrast to mice immunized with the full-length TcRpL7a, which produced high levels of IFN-γ, only low levels of IFN-γ or no IFN-γ were detected in cultures of splenocytes derived from mice immunized with truncated versions of the protein. After challenging with trypomastigotes, mice immunized with the TcRpL7a were partially protected against the infection whereas immunization with TcRpL7aΔRep did not alter parasitemia levels compared to controls. Strikingly, mice immunized with TcRpL7aRep displayed an exacerbated parasitemia compared to the other groups and 100% mortality after infection. Analyses of antibody production in mice that were immunized with TcRpL7aRep prior to infection showed a reduced humoral response to parasite antigens as well as against an heterologous antigen. In vitro proliferation assays with mice splenocytes incubated with different mitogens in the presence of TcRpL7aRep resulted in a drastic inhibition of B-cell proliferation and antibody production. Taken together, these results indicate that the repeat domain of TcRpL7a acts as an immunosuppressive factor that down regulates the host B-cell response against parasite antigens favoring parasite multiplication in the mammalian host.

Dataset Information

Modulation of cardiocyte functional activity by antibodies against trypanosoma cruzi ribosomal P2 protein C terminus.

Publications

Modulation of cardiocyte functional activity by antibodies against trypanosoma cruzi ribosomal P2 protein C terminus.

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