Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares, Rodrigo P.; Torrecilhas, Ana Claúdia; Assis, Rafael Ramiro de; Rocha, Marcele Neves; Castro, Felipe A. Moura e; Freitas, Gustavo F.; Murta, Silvane Maria Fonseca; Santos, Sara Lopes dos; Marques, Alexandre F.; Almeida, Igor C.; Romanha, Álvaro J.

doi:10.4269/ajtmh.2012.12-0015

Cited by 34 publications

(38 citation statements)

References 67 publications

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“…In this regard, previous work has described stage dependency in cruzipain expression in RA (63) and higher representation of trans-sialidase in more virulent strains (64). Emerging evidence also demonstrates that individual strains can elicit different proinflammatory responses through mechanisms involving GPI-associated mucins (65). Thus, low expression of danger signals such as GPI-associated mucins, cruzipain, and/or trans-sialidase may explain preferential reprograming of DC phenotype by different strains (49) and subsequent regulation of anti-parasite immunity.…”

Section: Discussionmentioning

confidence: 86%

Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1–Dependent Mechanisms

Poncini

Ilarregui

Batalla

et al. 2015

The Journal of Immunology

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Galectin-1 (Gal-1), an endogenous glycan-binding protein, is widely distributed at sites of inflammation and microbial invasion. Despite considerable progress regarding the immunoregulatory activity of this lectin, the role of endogenous Gal-1 during acute parasite infections is uncertain. In this study, we show that Gal-1 functions as a negative regulator to limit host-protective immunity following intradermal infection with Trypanosoma cruzi. Concomitant with the upregulation of immune inhibitory mediators, including IL-10, TGF-β1, IDO, and programmed death ligand 2, T. cruzi infection induced an early increase of Gal-1 expression in vivo. Compared to their wild-type (WT) counterpart, Gal-1–deficient (Lgals1−/−) mice exhibited reduced mortality and lower parasite load in muscle tissue. Resistance of Lgals1−/− mice to T. cruzi infection was associated with a failure in the activation of Gal-1–driven tolerogenic circuits, otherwise orchestrated by WT dendritic cells, leading to secondary dysfunction in the induction of CD4+CD25+Foxp3+ regulatory T cells. This effect was accompanied by an increased number of CD8+ T cells and higher frequency of IFN-γ–producing CD4+ T cells in muscle tissues and draining lymph nodes as well as reduced parasite burden in heart and hindlimb skeletal muscle. Moreover, dendritic cells lacking Gal-1 interrupted the Gal-1–mediated tolerogenic circuit and reinforced T cell–dependent anti-parasite immunity when adoptively transferred into WT mice. Thus, endogenous Gal-1 may influence T. cruzi infection by fueling tolerogenic circuits that hinder anti-parasite immunity.

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Section: Discussionmentioning

confidence: 86%

Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1–Dependent Mechanisms

Poncini

Ilarregui

Batalla

et al. 2015

The Journal of Immunology

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“…Although O -glycans of GPI-mucins from the insect-derived parasite forms have been well characterized in several parasite strains and genotypes, the exact structural information of most O -glycans for the mammal-dwelling tGPI-mucins remains unknown. Partial structural analysis and immunoassays have revealed that many of these trypomastigote-derived GPI-mucin (tGPI-mucin) O -glycans contain a terminal α-Gal residue, which is non-reducing and conserved on tGPI-mucins from at least four major Chagas disease causing T. cruzi genotypes [15, 60, 61]. These tGPI-mucin glycans are predominantly branched, and highly heterogeneous with different connectivities of the terminal α-Gal moiety to another sugar unit [12, 62].…”

Section: Resultsmentioning

confidence: 99%

Enhancing glycan isomer separations with metal ions and positive and negative polarity ion mobility spectrometry-mass spectrometry analyses

et al. 2016

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Glycomics has become an increasingly important field of research since glycans play critical roles in biology processes ranging from molecular recognition and signaling to cellular communication. Glycans often conjugate with other biomolecules, such as proteins and lipids, and alter their properties and functions, so glycan characterization is essential for understanding the effects they have on cellular systems. However, the analysis of glycans is extremely difficult due to their complexity and structural diversity (i.e., the number and identity of monomer units, and configuration of their glycosidic linkages and connectivities). In this work, we coupled ion mobility spectrometry with mass spectrometry (IMS-MS) to characterize glycan standards and biologically important isomers of synthetic αGal-containing O-glycans including glycotopes of the protozoan parasite Trypanosoma cruzi, which is the causative agent of Chagas disease. IMS-MS results showed significant differences for the glycan structural isomers when analyzed in positive and negative polarity and complexed with different metal cations. These results suggest that specific metal ions or ion polarities could be used to target and baseline separate glycan isomers of interest with IMS-MS.

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“…Although T. cruzi populations display differential virulence and pathogenic characteristics, genetic markers linked with the evolution of the infection and their outcomes have not been identified to date. Different efforts have been made to find virulence factors that correlate with the current parasite classification [37], [44]–[46]. A recent study [47] has shown differential expression of 29 out of 261 proteins that are overexpressed in T. cruzi stocks belonging to a given DTU.…”

Section: Discussionmentioning

confidence: 99%

Differential Distribution of Genes Encoding the Virulence Factor Trans-Sialidase along Trypanosoma cruzi Discrete Typing Units

et al. 2013

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Trypanosoma cruzi the agent of Chagas disease is a monophyletic but heterogeneous group conformed by several Discrete Typing Units (DTUs) named TcI to TcVI characterized by genetic markers. The trans-sialidase (TS) is a virulence factor involved in cell invasion and pathogenesis that is differentially expressed in aggressive and less virulent parasite stocks. Genes encoding TS-related proteins are included in a large family divided in several groups but only one of them contains TS genes. Two closely related genes differing in a T/C transition encode the enzymatically active TS (aTS) and a lectin-like TS (iTS). We quantified the aTS/iTS genes from TcII and TcVI aggressive and TcI low virulent strains and found variable aTS number (1–32) per haploid genome. In spite of being low TS enzyme-expressers, TcI strains carry 28–32 aTS gene copies. The intriguing absence of iTS genes in TcI strains together with the presence of aTS/iTS in TcII and TcVI strains (virulent) were observed. Moreover, after sequencing aTS/iTS from 38 isolates collected along the Americas encompassing all DTUs, the persistent absence of the iTS gene in TcI, TcIII and TcIV was found. In addition, the sequence clustering together with T/C transition analysis correlated to DTUs of T. cruzi. The consistence of TS results with both evolutionary genome models proposed for T. cruzi, namely the “Two Hybridization” and the “Three Ancestor” was discussed and reviewed to fit present findings. Parasite stocks to attempt genetic KO or to assay the involvement of iTS in parasite biology and virulence are finally available.

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Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Abstract: Abstract. The glycosylphosphatidylinositol (GPI

Cited by 34 publications

References 67 publications

Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1–Dependent Mechanisms

Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1–Dependent Mechanisms

Enhancing glycan isomer separations with metal ions and positive and negative polarity ion mobility spectrometry-mass spectrometry analyses

Differential Distribution of Genes Encoding the Virulence Factor Trans-Sialidase along Trypanosoma cruzi Discrete Typing Units

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