Trypanosoma cruzi cleaves galectin-3 N-terminal domain to suppress its innate microbicidal activity

Abstract

Summary Galectin-3 is the best-characterized member of galectins, an evolutionary conserved family of galactoside-binding proteins that play central roles in infection and immunity, regulating inflammation, cell migration and cell apoptosis. Differentially expressed by cells and tissues with immune privilege, they bind not only to host ligands, but also to glycans expressed by pathogens. In this regard, we have previously shown that human galectin-3 recognizes several genetic lineages of the protozoan parasite Trypanosoma cruzi, the causal agent of Chagas’ disease or American trypanosomiasis. Herein we describe a molecular mechanism developed by T. cruzi to proteolytically process galectin-3 that generates a truncated form of the protein lacking its N-terminal domain – required for protein oligomerization – but still conserves a functional carbohydrate recognition domain (CRD). Such processing relies on specific T. cruzi proteases, including Zn-metalloproteases and collagenases, and ultimately conveys profound changes in galectin-3-dependent effects, as chemical inhibition of parasite proteases allows galectin-3 to induce parasite death in vitro. Thus, T. cruzi might have established distinct mechanisms to counteract galectin-3-mediated immunity and microbicide properties. Interestingly, non-pathogenic T. rangeli lacked the ability to cleave galectin-3, suggesting that during evolution two genetically similar organisms have developed different molecular mechanisms that, in the case of T. cruzi, favoured its pathogenicity, highlighting the importance of T. cruzi proteases to avoid immune mechanisms triggered by galectin-3 upon infection. This study provides the first evidence of a novel strategy developed by T. cruzi to abrogate signalling mechanisms associated with galectin-3-dependent innate immunity.

Chimeric galectin-3 and collagens: Biomarkers and potential therapeutic targets in fibroproliferative diseases

“…To neutralize the microbicidal properties of galectin-3, protozoan parasites Trypanosoma cruzi and Leishmania major have developed molecular mechanisms to proteolytically cleave galecin-3 at its N terminus. The cleaved galectin-3 retained the carbohydrate-binding capacity but failed to induce the immune response ( 135 , 136 ). In a recent report, Zhao et al.…”

Galectins in Chagas Disease: A Missing Link Between Trypanosoma cruzi Infection, Inflammation, and Tissue Damage

“…This phenomenon raised the question of possible causes and mechanisms through which T. cruzi affects lectin structure. Pineda et al (2020) demonstrated that parasite death induced by long-term interactions between galectin-3 and T. cruzi is avoided by cleavage of the lectin N -terminal domain. Through this mechanism, the parasite likely counteracts galectin-3-driven immunity and host microbicidal activity, highlighting a possible strategy developed by parasites to survive inside mammalian hosts ( Pineda et al, 2020 ).…”

Galectina-3 controla a proliferação intracelular de Toxoplasma gondii em células trofoblásticas humanas (linhagem BeWo)

“…Além disso, Gal-3 reconhece o parasito T. cruzi e dessa forma proporciona a morte do parasito. Essa molécula aparenta ter tanta importância no controle de T. cruzi que o próprio parasito, para evadir dos mecanismos imunológicos desencadeados por Gal-3 durante a infecção, altera a estrutura molecular da galectina, anulando assim os mecanismos de sinalização associados à imunidade inata que são desencadeados por esta leucina (PINEDA et al, 2015;PINEDA et al, 2020).…”