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

Abstract

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.

How Does the Main Infective Stage ofT. cruziEnter and Avoid Degradation in Host Cells? A Description of the Pathways and Organelles Involved on These Processes

“…In relation to gp85/transsialidase, San Francisco and colleagues [40] demonstrate that this protein plays a fundamental importance in invasion since its depletion causes a decrease in T. cruzi virulence. The same type of result was reported by Pascuale et al [41] since inactive TS expression in trypomastigotes of a strain that does not express these TS (iTS null) allowed a better invasion and increase of the parasitic load in mice demonstrating that the inactive form may act alternatively or complementing the active TS in pathogenesis.…”

The RNA-binding protein TcUBP1 up-regulates an RNA regulon for a cell surface–associated Trypanosoma cruzi glycoprotein and promotes parasite infectivity

“…A comparative transcriptome profiling revealed that the CL-14 T. cruzi clone, which shows reduced expression of gene families encoding surface proteins-such as trans-sialidases and mucins-is associated with a nonvirulent phenotype (46). Likewise, transfection of noninfective T. cruzi strains with virulence factors such as inactive trans-sialidases leads to the generation of infective trypomastigotes (55). These findings strongly suggest that RBPs are involved in the modulation of expression of virulence factors affecting T. cruzi infectivity.…”

Exploring the Genomic Landscape of the GP63 family inTrypanosoma cruzi: Evolutionary Dynamics and Functional Peculiarities

“…However, it should be noted that these proteins could have other functions, as has been described for the trans-sialidase family, a family that should be renamed because most of its members have no enzymatic activity due to a mutation in the active site (26). However, these proteins retain other important functions by facilitating interaction with host cell receptors, promoting signaling and cell invasion of trypomastigote forms (27).…”