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Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27 Page 11 of 20

Role of the VE in Chagas disease
T. cruzi infects various types of cells including cardiac myocytes, GI-tract, smooth muscle cells, and the
VE [95,153] . The VE plays a key role in the dissemination of T. cruzi, as parasites engage ECs during the initial
stages of infection [85,86] . As the infection progresses, VE release inflammatory molecules by direct physical
disruption of ECs, and parasites undergo trans-endothelial migration with the help of the parasite protease,
cruzipain [85,87,88] . Cruzipain cleaves the human kininogen into bradykinin, an inflammatory mediator
of endothelial permeability [85,154,155] . Studies have shown that T. cruzi induces ECs release of vasoactive
molecules endothelin-1, pro-inflammatory cytokines (IL-1β, IL-6, and TNF-a), and thromboxane A2,
which trigger the production of iNOS and nitrosative stress [89-92] . Moreover, increased levels of TNF-a
[92]
exacerbate endothelial COX-2/TXA2/TP/superoxide signaling . The infection of T. cruzi also activates the
[95]
NF-kB that accumulates in the nucleus and activates many genes specific to endothelial pathophysiology .
In addition to the vascular damage, T. cruzi invades VE through the secretion of neuraminidase that
removes sialic acid from the infected ECs [156,157] . Collectively, all of these factors compromise the activity
of ECs and cause vasculopathy, as demonstrated by vasospasm, focal ischemia, reduction in the blood
flow, increased platelet aggregation, and elevated levels of thromboxane A (2) and endothelin-1 [89,158,159] .
Studies have shown that T. cruzi-infected ECs secrete endothelin-1 and interleukin-1beta (IL-1β), which
activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) and NF-kB, resulting in the expression
of cyclin-D1 in uninfected smooth muscle cells [93-95] . The activation of these pathways involved in the
interaction between T. cruzi and the VE are likely to play a major role in the inflammatory responses after
vascular injury and endothelial dysfunction and could be potential targets for therapies to control parasite
dissemination [65,85] .

It is estimated that 10%-30% of patients infected with T. cruzi progress to the chronic stage manifested
by cardiomyopathy and prothrombotic/inflammatory status [160] . Pathophysiological mechanisms such as
activation of the endothelium and microvascular alterations occur during the cardiac damage. It is known
that thromboxane A2 increases platelet aggregation and that inhibiting the formation of thromboxane A2
by aspirin alters the course of Chagas disease in both acute and chronic phases [161] . Benznidazole, a widely
used drug for the treatment of Chagas disease, also acts by preventing endothelial damage caused by
T. cruzi [162] . Cholesterol-lowering drugs such as simvastatin have been shown to decrease the endothelial
activation and, in combination with benznidazole, improve the pathophysiological condition of chronic
Chagas disease patients [163] . Recent discoveries have provided insights into how T. cruzi escapes the BBB
and rapidly migrates across the ECs without disrupting the integrity of the monolayer or altering the
[85]
permeability. Coates et al. identified that this process is facilitated by bradykinin and CCL2, which may
be considered in the development of new therapeutic strategies for Chagas disease.

Role of exosomes in Chagas disease
Parasite and host cell exosomes play a role in the pathogenesis in Chagas disease. The release of an elevated
number of exosomes is essential for host-parasite interaction, intercellular communication, and enhanced
parasite survival [120] . The infection of T. cruzi induces blood cells to release exosomes through a Ca -
2+
dependent manner [164] . The released exosomes protect extracellular trypomastigotes from complement-
mediated lysis by binding to C3 convertase on the T. cruzi surface and inhibiting C3 cleavage [115-117] .
Exosomes also aid the parasites to invade the host cells through the expression of TGF-β. The
communication between cells takes place through the release of exosomal contents including cytokines,
peptides, hormones, microRNA, and numerous bioactive substances, which act as a function of innate
immunity [165,166] . Exosomes released by T. cruzi promote cell invasion and parasite survival by modulating
the innate immune system and producing several virulence factors including the glycoprotein 85 (gp85),
trans-sialidase, phosphatase, and the soluble proteins [116,119,120,167] . Thus, the exosomes released by the host
cells and parasites during infection play a vital role in the invasion of the innate immune system, parasite
survival, and the establishment of infection in Chagas disease.