The Trypanosoma cruzi Surface, a Nanoscale Patchwork Quilt

Mucci, Juan; Lantos, Andrés B.; Buscaglia, Carlos A.; Leguizamón, María Susana; Campetella, Oscar

doi:10.1016/j.pt.2016.10.004

Cited by 46 publications

(62 citation statements)

References 97 publications

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“…When GO enrichment was examined for the differential expression from amastigotes at 96 hpi to trypomastigotes, an expected enrichment of protein kinase activity (GO:0004672) and hexose transport (GO:0008645) was identified amongst the upregulated genes in both strains. These finding are in agreement with data that showed that glucose is the main energy source for the parasite in the bloodstream and also with increased protein modification, such as phosphorylation of MASPs, that is required for the abundant expression of cell surface glycoproteins in trypomastigotes [ 12 , 20 , 21 , 22 ]. Also consistent with a decreased metabolism and macromolecular biosynthesis of the non-replicative trypomastigotes, down-regulated genes in both strains were enriched in protein translation (GO:0006412), protein folding (GO:0006457), ion transport (GO:0006811), oxidoreductase activity (GO:0016491), lipid biosynthesis (GO:0008610) and chromosome organization (GO:0051276).…”

Section: Resultssupporting

confidence: 92%

Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection

et al. 2017

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Trypanosoma cruzi, the protozoan that causes Chagas disease, has a complex life cycle involving several morphologically and biochemically distinct stages that establish intricate interactions with various insect and mammalian hosts. It has also a heterogeneous population structure comprising strains with distinct properties such as virulence, sensitivity to drugs, antigenic profile and tissue tropism. We present a comparative transcriptome analysis of two cloned T. cruzi strains that display contrasting virulence phenotypes in animal models of infection: CL Brener is a virulent clone and CL-14 is a clone that is neither infective nor pathogenic in in vivo models of infection. Gene expression analysis of trypomastigotes and intracellular amastigotes harvested at 60 and 96 hours post-infection (hpi) of human fibroblasts revealed large differences that reflect the parasite’s adaptation to distinct environments during the infection of mammalian cells, including changes in energy sources, oxidative stress responses, cell cycle control and cell surface components. While extensive transcriptome remodeling was observed when trypomastigotes of both strains were compared to 60 hpi amastigotes, differences in gene expression were much less pronounced when 96 hpi amastigotes and trypomastigotes of CL Brener were compared. In contrast, the differentiation of the avirulent CL-14 from 96 hpi amastigotes to extracellular trypomastigotes was associated with considerable changes in gene expression, particularly in gene families encoding surface proteins such as trans-sialidases, mucins and the mucin associated surface proteins (MASPs). Thus, our comparative transcriptome analysis indicates that the avirulent phenotype of CL-14 may be due, at least in part, to a reduced or delayed expression of genes encoding surface proteins that are associated with the transition of amastigotes to trypomastigotes, an essential step in the establishment of the infection in the mammalian host. Confirming the role of members of the trans-sialidase family of surface proteins for parasite differentiation, transfected CL-14 constitutively expressing a trans-sialidase gene displayed faster kinetics of trypomastigote release in the supernatant of infected cells compared to wild type CL-14.

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Section: Resultssupporting

confidence: 92%

Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection

et al. 2017

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“…Among them the trans -sialidase (TS), an enzyme expressed and shed by the trypomastigote stage, has arisen as one of particular relevance due to its effect on the immune system and involvement in the interaction/invasion of the host cell, playing also a central role in the parasite biology (Oliveira et al, 2014 ). T. cruzi is unable to synthesize sialic acids de novo and thus, the surface membrane glycoconjugates are sialylated by TS that obtain this sugar from the host glycoconjugates (Mucci et al, 2017 ). Acquisition of the sialyl residue allows the parasite to survive in blood and disseminate the infection.…”

Section: Introductionmentioning

confidence: 99%

Inactive trans-Sialidase Expression in iTS-null Trypanosoma cruzi Generates Virulent Trypomastigotes

Pascuale

Burgos

Postan

et al. 2017

Front. Cell. Infect. Microbiol.

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Disclosing virulence factors from pathogens is required to better understand the pathogenic mechanisms involved in their interaction with the host. In the case of Trypanosoma cruzi several molecules are associated with virulence. Among them, the trans-sialidase (TS) has arisen as one of particular relevance due to its effect on the immune system and involvement in the interaction/invasion of the host cells. The presence of conserved genes encoding for an inactive TS (iTS) isoform is puzzlingly restricted to the genome of parasites from the Discrete Typing Units TcII, TcV, and TcVI, which include highly virulent strains. Previous in vitro results using recombinant iTS support that this isoform could play a different or complementary pathogenic role to that of the enzymatically active protein. However, direct evidence involving iTS in in vivo pathogenesis and invasion is still lacking. Here we faced this challenge by transfecting iTS-null parasites with a recombinant gene that allowed us to follow its expression and association with pathological events. We found that iTS expression improves parasite invasion of host cells and increases their in vivo virulence for mice as shown by histopathologic findings in heart and skeletal muscle.

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“…Microscopy-based experiments showed that TSSA-CL, as previously reported for other trypomastigote surface markers [ 19 ], does not co-localize with sialylated tGPI-mucins. The punctate pattern observed for TSSA-CL builds upon our hypothesis of the trypomastigote membrane as a highly organized structure made up of multiple and discrete nanoscale domains bearing different protein composition [ 48 ]. Further affinity fractionation experiments and whole-parasite butan-1-ol partition assays definitely established that TSSA and tGPI-mucins are completely different species.…”

Section: Discussionmentioning

confidence: 72%

The Trypomastigote Small Surface Antigen (TSSA) regulates Trypanosoma cruzi infectivity and differentiation

et al. 2017

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BackgroundTSSA (Trypomastigote Small Surface Antigen) is an antigenic, adhesion molecule displayed on the surface of Trypanosoma cruzi trypomastigotes. TSSA displays substantial sequence identity to members of the TcMUC gene family, which code for the trypomastigote mucins (tGPI-mucins). In addition, TSSA bears sequence polymorphisms among parasite strains; and two TSSA variants expressed as recombinant molecules (termed TSSA-CL and TSSA-Sy) were shown to exhibit contrasting features in their host cell binding and signaling properties.Methods/Principle findingsHere we used a variety of approaches to get insights into TSSA structure/function. We show that at variance with tGPI-mucins, which rely on their extensive O-glycoslylation to achieve their protective function, TSSA seems to be displayed on the trypomastigote coat as a hypo-glycosylated molecule. This has a functional correlate, as further deletion mapping experiments and cell binding assays indicated that exposition of at least two peptidic motifs is critical for the engagement of the ‘adhesive’ TSSA variant (TSSA-CL) with host cell surface receptor(s) prior to trypomastigote internalization. These motifs are not conserved in the ‘non-adhesive’ TSSA-Sy variant. We next developed transgenic lines over-expressing either TSSA variant in different parasite backgrounds. In strict accordance to recombinant protein binding data, trypomastigotes over-expressing TSSA-CL displayed improved adhesion and infectivity towards non-macrophagic cell lines as compared to those over-expressing TSSA-Sy or parental lines. These phenotypes could be specifically counteracted by exogenous addition of peptides spanning the TSSA-CL adhesion motifs. In addition, and irrespective of the TSSA variant, over-expression of this molecule leads to an enhanced trypomastigote-to-amastigote conversion, indicating a possible role of TSSA also in parasite differentiation.Conclusion/SignificanceIn this study we provided novel evidence indicating that TSSA plays an important role not only on the infectivity and differentiation of T. cruzi trypomastigotes but also on the phenotypic variability displayed by parasite strains.

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The Trypanosoma cruzi Surface, a Nanoscale Patchwork Quilt

Cited by 46 publications

References 97 publications

Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection

Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection

Inactive trans-Sialidase Expression in iTS-null Trypanosoma cruzi Generates Virulent Trypomastigotes

The Trypomastigote Small Surface Antigen (TSSA) regulates Trypanosoma cruzi infectivity and differentiation

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