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

Abstract

Trypanosoma cruzi, the etiological agent of Chagas disease, is an intracellular parasite that targets specific proteins of the host cell resulting in the generation of a unique parasitophorous vacuole (PV). As an intracellular parasite, T. cruzi interacts with cells from the mammalian host. Here we review aspects related with the binding of the main infective developmental stage (trypomastigote) to the host cell and its recognition by surface-exposed ligands/receptors. This process involves numerous signaling pathways and culminates in the entry of the parasite and modifications in both cells. The invasion of trypomastigotes occurs through multiple endocytic process, assembly of the PV, interaction of this vacuole with the endolysosomal system, lysis of the PV membrane, and multiplication of amastigotes within the cell in direct contact with host cell organelles.assumed that replicating epimastigotes present in the insect gut are not infective to mammalian host. During the vector infection (caused by a hematophagous insect of the family Reduviidae), metacyclic trypomastigotes [8], which penetrate the vertebrate host (several mammals, including man), are released along with their excreta coming in contact with conjunctiva areas or through small lesions in the own site of the bite (favored by the itch caused after the insect's bite). In turn, metacyclic trypomastigotes are able to invade virtually all cell types in the vertebrate host, especially muscle cells, fibroblasts, and macrophages [6]. At this moment, the intracellular cycle of T. cruzi begins, where the firing of several signaling cascades culminates with the closure of the parasitophorous vacuole (PV) where the parasite is found [9,10]. After the PV closure, the process of differentiation of the parasite from the trypomastigote stage to the amastigote stage begins. At the same time, fragmentation of the PV membrane takes place most probably due to the increased concentration of the Tc-Tox perforin-like protein produced by the parasite [11]. After the destruction of the vacuole, the parasite, in the process of differentiation, will be found in the cytoplasm of the host cell where it will initiate its multiplication and subsequent differentiation for trypomastigotes culminating in the rupture of the host cell (Figure 1) [13]. The whole process of formation of the parasitophorous vacuole until its rupture counts on the participation of several organelles of the host cell. Among these, the best characterized is the participation of host cell endosomes and lysosomes. It is the fusion of these organelles with the PV membrane that probably allows the increase or expansion of the PV. In addition, this process is also responsible for the generation of an acidic environment within the PV, which probably will potentiate the action of Tc-Tox and PV membrane fragmentation [13]. Wilkowsky and colleagues [14] have shown that early and late endosomes were critical for vacuole formation. In addition, other organelles responsible for the production of proteins and energy (...

First case report on molecular detection of Trypanosoma lewisi in an urban rat in Kelantan, Malaysia: An accidental finding

“…The presence of T. lewisi polymorphism in the blood of rats in our study shows the establishment of an infective stage with the presence of both epimastigotes (development stage) and trypomastigotes (infectious stage; adult stage). This finding is interesting because epimastigotes are usually seen in the midgut of invertebrate vectors such as flies [ 19 ] and rarely in maintenance hosts [ 20 ]. It may be possible that stages of T. lewisi development occur in both maintenance host and invertebrate vectors compared to its closest relatives, such as Trypanosoma cruzi [ 21 ].…”

Heparan sulfate proteoglycan triggers focal adhesion kinase signaling during Trypanosoma cruzi invasion

“…(17,18) Activation of signaling pathways during the initial parasite-host cell interface stage promotes T. cruzi entry by cytoskeleton-dependent or -independent processes. (5) FAK, which is involved in cytoskeleton regulation, (19) is activated during T. cruzi cardiomyocyte invasion. (7) In the present study, we identified HSPG as protagonists in triggering the FAK signaling pathway during T. cruzi cell entry.…”

“…(5) Different T. cruzi invasion mechanisms involving IP3-kinase activation, lysosome recruitment (including oligopeptidase B and cruzipain-mediated), sphingomyelinase-mediated membrane repair and autophagic pathways, as well as host cell cytoskeleton mechanisms, have been described. (5) Many cellular signaling pathways have been reported as driving parasite entrance, including protein kinase activation. (5) The activation of focal adhesion kinase (FAK), a non-receptor tyrosine kinase, may be subverted by diverse intracellular pathogens, (6) including T. cruzi.…”

“…(5) Many cellular signaling pathways have been reported as driving parasite entrance, including protein kinase activation. (5) The activation of focal adhesion kinase (FAK), a non-receptor tyrosine kinase, may be subverted by diverse intracellular pathogens, (6) including T. cruzi. (7) FAK comprises three domains, a kinase domain flanked by two non-catalytic domains, the FERM (ezrin-radixin-moesin) domain at the N-terminus and the focal adhesion targeting (FAT) domain, a kinase domain regulator, (8) at the C-terminus, which binds to focal adhesion proteins such as paxillin and talin, as well as docking sites for Src homology 3 (SH3) domain-containing proteins.…”

Perspectives for a new drug candidate for Chagas disease therapy

“… 3 Thus, the trypomastigotes invade all nucleated cells by an endocytic process mediated by multiple ligand/receptor and signaling systems. 4 Intracellularly, trypomastigotes escape from the parasitophorous vacuole, and convert to amastigote forms that are the multiplicative stage found in vertebrate hosts. After several binary division cycles, amastigotes differentiate back into trypomastigotes, which are the main forms released after the rupture of infected host cells.…”