Impact of the Extracellular Vesicles Derived From Trypanosoma cruzi: A Paradox in Host Response and Lipid Metabolism Modulation

Abstract

Chagas disease is a major public health problem, especially in the South and Central America region. Its incidence is related to poverty and presents a high rate of morbidity and mortality. The pathogenesis of Chagas disease is complex and involves many interactive pathways between the hosts and the Trypanosoma cruzi. Several factors have been implicated in parasite-host interactions, including molecules secreted by infected cells, lipid mediators and most recent, extracellular vesicles (EVs). The EVs of T. cruzi (EVsT) were reported for the first time in the epimastigote forms about 42 years ago. The EVsT are involved in paracrine communication during the infection and can have an important role in the inflammatory modulation and parasite escape mechanism. However, the mechanisms by which EVs employ their pathological effects are not yet understood. The EVsT seem to participate in the activation of macrophages via TLR2 triggering the production of cytokines and a range of other molecules, thus modulating the host immune response which promotes the parasite survival. Moreover, new insights have demonstrated that EVsT induce lipid body formation and PGE₂ synthesis in macrophages. This phenomenon is followed by the inhibition of the synthesis of pro-inflammatory cytokines and antigen presentation, causing decreased parasitic molecules and allowing intracellular parasite survival. Therefore, this mini review aims to discuss the role of the EVs from T. cruzi as well as its involvement in the mechanisms that regulate the host immune response in the lipid metabolism and its significance for the Chagas disease pathophysiology.

Keywords: Changas disease; T. cruzi; extracellular vesicles; infectious diseases; inflammation; lipid droplets; parasite replication; prostaglandin.

Figure 1

Schematic model summarizing the molecules involved on parasite-host cell interaction process and EVs secreted by trypomastigotes of Trypanosoma cruzi (A). Mechanisms of action triggered by T. cruzi, EVs and EVsT in macrophages (B). (A) Parasite exhibiting major components of its membrane associated with EVsT. Note the parasite cytoplasm containing microvesicles, exosomes, and lipid bodies (LBs). In detail, EVsT showing a lipid bilayer containing the main macromolecules carried by these structures, such as DNA, RNA, fatty acids, enzymes, mucin-associated surface proteins (MASP), among others. (B) T. cruzi internalized by macrophage (infected cell) induces LB formation and PGE₂ derived from LBs contributing to amastigote replication, as well as release of microvesicles from the host cell (EVs). We suggest that the EVsT from T. cruzi and EVs from infected host cells are also recognized by uninfected macrophages via TLR2 inducing LB formation and PGE₂ synthesis (dashed lines). However, further studies are needed to define the receptors and signaling responses induced upon EVs and EVsT-macrophage interaction and how these interactions/responses change as the exosome composition is modified during an infection. In general, T cruzi and/or EVs/EVsT via TLR2 active PPAR-y to translocate to nucleus, heterodimerize with RXR and binding to specific DNA response elements (PPRE) in target genes, altering the lipid metabolism and inducing LB formation. The PGE₂ (produced in LB_S via COX-2 enzyme activation) is a potent lipid mediator which reduces the host Th1 immune response (by inhibition of the TNF-α and IL-6 and induction of the IL-10) and down modulates the microbicidal function of the macrophage. In parallel, the activation of NK-κB also modulates the synthesis of cytokines. In detail, representation of the structure and composition of LB. Arachidonic acid (AA); cyclooxygenase -2 (COX-2), triacylglycerol (TAG), diacylglycerol (DAG), peroxisome proliferator-activated receptor-y response element (PPER).