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Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24.

ABSTRACT: Trypanosoma cruzi causes life-long disease after infection and leads to cardiac disease in 30% of infected individuals. After infection, the parasites are readily detectable in the blood during the first few days before disseminating to infect numerous cell types. Preliminary data suggested that the Tc24 protein that localizes to the T. cruzi membrane during all life stages possesses B-cell superantigenic properties. These antigens facilitate immune escape by interfering with antibody-mediated responses, particularly the avoidance of catalytic antibodies. These antibodies are an innate host defense mechanism present in the naive repertoire, and catalytic antibody-antigen binding results in hydrolysis of the target. We tested the B-cell superantigenic properties of Tc24 by comparing the degree of Tc24 hydrolysis by IgM purified from either Tc24 unexposed or exposed mice and humans. Respective samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, silver stained, and the degree of hydrolysis was measured. Data presented in this report suggest that the T. cruzi Tc24 is a B-cell superantigen based on the observations that 1) Tc24 was hydrolyzed by IgM present in serum of unexposed mice and humans and 2) exposure to Tc24 eliminated catalytic activity as early as 4 days after T. cruzi infection.

SUBMITTER: Gunter SM

PROVIDER: S-EPMC4710414 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24.

Gunter Sarah M SM Jones Kathryn M KM Zhan Bin B Essigmann Heather T HT Murray Kristy O KO Garcia Melissa N MN Gorchakov Rodion R Bottazzi Maria Elena ME Hotez Peter J PJ Brown Eric L EL

The American journal of tropical medicine and hygiene 20151123 1

Trypanosoma cruzi causes life-long disease after infection and leads to cardiac disease in 30% of infected individuals. After infection, the parasites are readily detectable in the blood during the first few days before disseminating to infect numerous cell types. Preliminary data suggested that the Tc24 protein that localizes to the T. cruzi membrane during all life stages possesses B-cell superantigenic properties. These antigens facilitate immune escape by interfering with antibody-mediated r ...[more]

PMID: 26598565

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Project description:(1) Background: Chagas disease is the main neglected tropical disease in America. It is estimated that around 6 million people are currently infected with the parasite in Latin America, and 25 million live in endemic areas with active transmission. The disease causes an estimated economic loss of USD 24 billion dollars annually, with a loss of 75,200 working years per year of life; it is responsible for around ~12,000 deaths annually. Although Mexico is an endemic country that recorded 10,186 new cases of Chagas disease during the period of 1990-2017, few studies have evaluated the genetic diversity of genes that could be involved in the prophylaxis and/or diagnosis of the parasite. One of the possible candidates proposed as a vaccine target is the 24 kDa trypomastigote excretory-secretory protein, Tc24, whose protection is linked to the stimulation of T. cruzi-specific CD8+ immune responses. (2) Methods: The aim of the present study was to evaluate the fine-scale genetic diversity and structure of Tc24 in T. cruzi isolates from Mexico, and to compare them with other populations reported in the Americas with the aim to reconsider the potential role of Tc24 as a key candidate for the prophylaxis and improvement of the diagnosis of Chagas disease in Mexico. (3) Results: Of the 25 Mexican isolates analysed, 48% (12) were recovered from humans and 24% (6) recovered from Triatoma barberi and Triatoma dimidiata. Phylogenetic inferences revealed a polytomy in the T. cruzi clade with two defined subgroups, one formed by all sequences of the DTU I and the other formed by DTU II-VI; both subgroups had high branch support. Genetic population analysis detected a single (monomorphic) haplotype of TcI throughout the entire distribution across both Mexico and South America. This information was supported by Nei's pairwise distances, where the sequences of TcI showed no genetic differences. (4) Conclusions: Given that both previous studies and the findings of the present work confirmed that TcI is the only genotype detected from human isolates obtained from various states of Mexico, and that there is no significant genetic variability in any of them, it is possible to propose the development of in silico strategies for the production of antigens that optimise the diagnosis of Chagas disease, such as quantitative ELISA methods that use this region of Tc24.

Project description:Contractile vacuole complexes are critical components of cell volume regulation and have been shown to have other functional roles in several free-living protists. However, very little is known about the functions of the contractile vacuole complex of the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, other than a role in osmoregulation. Identification of the protein composition of these organelles is important for understanding their physiological roles. We applied a combined proteomic and bioinfomatic approach to identify proteins localized to the contractile vacuole. Proteomic analysis of a T. cruzi fraction enriched for contractile vacuoles and analyzed by one-dimensional gel electrophoresis and LC-MS/MS resulted in the addition of 109 newly detected proteins to the group of expressed proteins of epimastigotes. We also identified different peptides that map to at least 39 members of the dispersed gene family 1 (DGF-1) providing evidence that many members of this family are simultaneously expressed in epimastigotes. Of the proteins present in the fraction we selected several homologues with known localizations in contractile vacuoles of other organisms and others that we expected to be present in these vacuoles on the basis of their potential roles. We determined the localization of each by expression as GFP-fusion proteins or with specific antibodies. Six of these putative proteins (Rab11, Rab32, AP180, ATPase subunit B, VAMP1, and phosphate transporter) predominantly localized to the vacuole bladder. TcSNARE2.1, TcSNARE2.2, and calmodulin localized to the spongiome. Calmodulin was also cytosolic. Our results demonstrate the utility of combining subcellular fractionation, proteomic analysis, and bioinformatic approaches for localization of organellar proteins that are difficult to detect with whole cell methodologies. The CV localization of the proteins investigated revealed potential novel roles of these organelles in phosphate metabolism and provided information on the potential participation of adaptor protein complexes in their biogenesis.

Dataset Information

Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24.

Publications

Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24.

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