Role of Inactive and Active Trypanosoma cruzi Trans-sialidases on T Cell Homing and Secretion of Inflammatory Cytokines

Abstract

Trans-sialidase from Trypanosoma cruzi (Tc-TS) belongs to a superfamily of proteins that may have enzymatic activity. While enzymatically active members (Tc-aTS) are able to transfer sialic acid from the host cell sialyl-glycoconjugates onto the parasite or to other molecules on the host cell surface, the inactive members (Tc-iTS) are characterized by their lectinic properties. Over the last 10 years, several papers demonstrated that, individually, Tc-aTS or Tc-iTS is able to modulate several biological events. Since the genes encoding Tc-iTS and Tc-aTS are present in the same copy number, and both proteins portray similar substrate-specificities as well, it would be plausible to speculate that such molecules may compete for the same sialyl-glycan structures and govern numerous immunobiological phenomena. However, their combined effect has never been evaluated in the course of an acute infection. In this study, we investigated the ability of both proteins to modulate the production of inflammatory signals, as well as the homing of T cells to the cardiac tissue of infected mice, events that usually occur during the acute phase of T. cruzi infection. The results showed that the intravenous administration of Tc-iTS, but not Tc-aTS protected the cardiac tissue from injury caused by reduced traffic of inflammatory cells. In addition, the ability of Tc-aTS to modulate the production of inflammatory cytokines was attenuated and/or compromised when Tc-iTS was co-injected in the same proportions. These results suggest that although both proteins present structural similarities and compete for the same sialyl-glycan epitopes, they might present distinct immunomodulatory properties on T cells following T. cruzi infection.

Theft and Reception of Host Cell's Sialic Acid: Dynamics of Trypanosoma Cruzi Trans-sialidases and Mucin-Like Molecules on Chagas' Disease Immunomodulation

“…Although it has been known for more than twenty years that both iTS and aTS have almost identical structures and compete for the same substrate (40, 42, 44), little is known about the biological effects triggered by iTS during T. cruzi infection.…”

“…Although the molecular mechanisms have not been elucidated, the authors claim that iTS might play a different or complementary pathogenic role to aTS (45). Recently, our group demonstrated that mice treated with an elevated (non-physiological) concentration of recombinant iTS showed a compromise of T cells homing to the cardiac tissue during T. cruzi -infection (44). Since iTS is capable of recognizing SIA-containing glycans, which are carried by many glycoproteins involved in leukocyte extravasation through activated venular walls (66–68) it would be plausible to speculate that iTS, through its lectinic property, may bind to sialylated peripheral homing receptors, impairing the homing of inflammatory cells to the target tissues.…”

“…The poor development of genetic tools to directly dissect the biological roles displayed by either iTS or aTS, leads researchers towards alternative approaches for this technical deadlock. The use of both recombinant T. cruzi- iTS and aTS, separately or together, may provide a good way for studying the effects triggered by both TS proteins (44). Over the last fifteen years, studies demonstrated that when administered separately, both iTS and aTS elicit similar biological effects (42, 69, 70).…”

“…However, until recently, there was no published data showing their combined effects. Immunological studies carried out by our group revealed that in T. cruzi -infected mice, the intravenous administration of high concentrations of recombinant aTS was able to modulate the expression of inflammatory signals by splenic T cells (44). Nevertheless, when both recombinant iTS and aTS were injected in equivalent amounts, such phenomena were significantly compromised (44).…”

The Glycan Structure of T. cruzi mucins Depends on the Host. Insights on the Chameleonic Galactose

“…Once in the cell, trypomastigotes accumulate in a parasitophorus vacuole (PV) formed by fusion with the host lysosome, an essential step in order to evade the immune response of the host [ 12 , 13 ]. Several biological processes take place in the PV, and one of them is due to the action of the T. cruzi trans-sialidase (TcTS), referred later in this review, which mediates parasite escape from PVs to cytosol [ 14 , 15 ]. In the PV, the parasites start to transform into amastigotes, and differentiation is completed in the cytosol.…”