The role of vascular endothelium and exosomes in human protozoan parasitic diseases

Abstract

The vascular endothelium is a vital component in maintaining the structure and function of blood vessels. The endothelial cells (ECs) mediate vital regulatory functions such as the proliferation of cells, permeability of various tissue membranes, and exchange of gases, thrombolysis, blood flow, and homeostasis. The vascular endothelium also regulates inflammation and immune cell trafficking, and ECs serve as a replicative niche for many bacterial, viral, and protozoan infectious diseases. Endothelial dysfunction can lead to vasodilation and pro-inflammation, which are the hallmarks of many severe diseases. Exosomes are nanoscale membrane-bound vesicles that emerge from cells and serve as important extracellular components, which facilitate communication between cells and maintain homeostasis during normal and pathophysiological states. Exosomes are also involved in gene transfer, inflammation and antigen presentation, and mediation of the immune response during pathogenic states. Protozoa are a diverse group of unicellular organisms that cause many infectious diseases in humans. In this regard, it is becoming increasingly evident that many protozoan parasites (such as Plasmodium, Trypanosoma, Leishmania, and Toxoplasma) utilize exosomes for the transfer of their virulence factors and effector molecules into the host cells, which manipulate the host gene expression, immune responses, and other biological activities to establish and modulate infection. In this review, we discuss the role of the vascular endothelium and exosomes in and their contribution to pathogenesis in malaria, African sleeping sickness, Chagas disease, and leishmaniasis and toxoplasmosis with an emphasis on their actions on the innate and adaptive immune mechanisms of resistance.

Keywords: Vascular endothelium; exosomes; leishmaniasis; malaria; toxoplasmosis; trypanosomiasis.

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-κB in macrophages. The PTPs prevent macrophage activation by inhibiting the secretion of IFN-γ, 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-α, and IFN-γ 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-α, 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