**7. Apoptosis-like death in** *T. cruzi*

It may seem odd to think that single-celled organisms can undergo apoptosis themselves, but it is believed that this has benefits for the survival of the population and therefore of the species. Shortly after apoptosis was described in metazoans, Docampo et al., using transmission electron microscopy, observed cytoplasmic and nuclear features suggestive of apoptosis in epimastigotes of *T. cruzi* treated with β-lapachone,

## *Modulation of Host Cell Apoptosis by* Trypanosoma cruzi*: Repercussions in the Development… DOI: http://dx.doi.org/10.5772/intechopen.103740*

an o-naphthoquinone that inhibits the synthesis of DNA. Such alterations included plasma membrane blebbing, chromatin condensation, and mitochondrial membrane alterations [74]. In addition to Trypanosoma, apoptotic death has been described in other protozoan taxa such as *Plasmodium*, and *Leishmania* that show distinctive characteristics of apoptosis similar to those described in multicellular organisms; however, the mechanisms involved are not fully understood [75]. Since then, other research groups have reported the appearance of stress- and drug-induced apoptotic traits (DNA fragmentation, PS externalization, loss of mitochondrial membrane potential, and cytochrome-c release) in *T. cruzi* [76, 77] with phenotypic similarities between metazoan cell apoptosis and *T. cruzi* cell death, but also with important differences in the processes and molecules that participate in them. Although PS translocation is a remarkable apoptotic trait in mammalian cells, in *T. cruzi* seems to be a parasite strategy to counteract macrophage activation [78]. On the other hand, caspases, key participants in apoptosis, are not present in *T. cruzi*. Nevertheless, its genome contains the TcMCA3 and TcMCA5 genes that code for metacaspases, cysteine proteases structurally similar to caspases but, unlike the latter, they have specificity for basic amino acid residues and are dependent on millimolar concentrations of calcium [79, 80]. The TcMCA3 protein is expressed in the four main stages of the parasite (epimastigotes, metacyclic trypomastigotes, blood trypomastigotes, and amastigotes), while TcMCA 5 is only expressed in epimastigotes. Analysis performed by immunofluorescence has shown that the treatment of *T. cruzi* with human serum, to induce programmed cell death, provokes a change in the subcellular localization of both metacaspases translocating them to the nucleus [81]. It has been observed that the increase in the expression of TcMCA5 augments the sensitivity of epimastigotes to programmed cell death as compared with parasites that express it at physiological levels. For its part, TcMCA3 protects epimastigotes from natural cell death and seems to play an important role in the process of differentiation to infectious metacyclic trypomastigotes [81].

Another molecule that could play an important role in the regulation of apoptotic cell death in *T. cruzi* is the elongation factor-1 (EF-1). This molecule, usually found in the nucleus and cytoplasm of eukaryotic cells, is formed of two subunits (EF-1α and EF-βγδ), and plays an important role in protein synthesis and in processes such as mitosis and cell proliferation [82]. Using anti-TcEF-1α antibodies coupled with fluorescein isothiocyanate, it was possible to observe that TcEF-1α accumulates in the nucleus of *T. cruzi* epimastigotes cultured for more than 13 days, which also showed apoptotic traits [83]. Subsequent investigations revealed that changes in the expression levels of EF-1α modify the rate of apoptosis in a murine erythroleukemic cell line [84], which suggests that TcEF-1α could be a marker of apoptosis in *T. cruzi*. The similarities that have been found between mammalian apoptosis and the phenomenon observed in *T. cruzi* have led some researchers to call it "apoptosis-like cell death" [85]. Nevertheless, other authors have concluded that the type of death observed in *Trypanosoma* and other protozoan parasites does not have the characteristics of a regulated death, and it is more an incidental cell death or necrosis [86].
