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Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27 Page 13 of 20

Figure 1. Schematic representation of cellular and molecular mechanisms played by vascular endothelium (VE) and exosomes
in Plasmodium, Leishmania, Toxoplasma, and Trypanosoma spp. Infection. A: P. falciparum protein PfPTP-2 released through the
exosomes from infected red blood cells (RBCs) facilitates cell-to-cell communication and promotes the differentiation of sexual forms
of the parasites. P. falciparum erythrocyte membrane protein-1 (PfEMP1) and intercellular adhesion molecule-1 (ICAM-1) mediate the
adhesion of infected erythrocytes to the VE and placental syncytioblasts; B: Leishmania parasites transport glycoproteins such as GP63
into the host cells through exosomes and regulate the protein tyrosine phosphatases (PTPs) and transcription factors such as NF-kB
in macrophages. The PTPs prevent macrophage activation by inhibiting the secretion of IFN-g, IL-12, and nitric oxide (NO). Leishmania
infection also increases the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-
1) to initiate an inflammatory response after migrating the mononuclear cells and lymphocytes to the endothelial cells; C: T. gondii
parasites release exosomes, which contain HSP70 and CD63, as well as the T. gondii surface marker P30. These exosomes induce the
production of IL-12, TNF-a, and IFN-g and modulate macrophage activation; D: T. brucei releases exosomes that are deposited and fused
to RBCs. The virulence factors of exosomes result in RBC membrane alteration and anemia. In addition, T. brucei activates the vascular
endothelial cells by producing TNF-a, IL-6, and IL-8. The exosomes of T. cruzi contain C3 convertase binding protein, which helps the
++
parasites to escape the complement-mediated lysis. T. cruzi releases cruzipain and invades vascular endothelium through a Ca -
dependent mechanism

Thus, the exosomal components (proteases) of the trypanosome could be the promising targets to control
sleeping sickness [181] .

CONCLUDING REMARKS
Here, we discuss the important roles played by VE and exosomes in some major protozoan parasitic
diseases. Exosomes serve as a carrier of effector molecules that modulate the host immune response
in establishing infection. The content of exosomes provides an effectual means to control the protein
expression in both parasite and host cells. While parasite-derived exosomes play a key role in establishing
infections through intercellular communication and signaling mechanisms, the host-derived exosomes
also play a major role in the host-defense mechanism. Understanding the mechanism of the exosomal