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Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27 Page 7 of 20

miRNA Parasite Activates inflammatory responses in nearby [114]
macrophages in a TLR- and MyD88-dependent
manner. Interact and modulate host cells through gene
regulation
Chagas Exosome Infected blood Protects extracellular parasites from complement- [115-117]
disease cells mediated lysis by binding the C3 convertase on the
parasite surface and inhibiting C3 cleavage
Virulence factors and Parasite Helps parasites to invade host cells through the [118]
soluble proteins expression of transforming growth factor-beta (TGF-β)
Complement regulatory Parasite Enhances cell invasion and parasite survival by invading [119,120]
and inhibitory proteins the innate immune system
Avoids the complement system and increase the [121,122]
invasion of host cells
HAT Virulence factors and Parasite Activates the innate and acquired immune responses [123,124]
proteins (SRA) and induces rapid clearance of erythrocytes to cause
anemia and tissue damage
HAT: Human African trypanosomiasis; IL: interleukin; PAMPs: pathogen associated molecular patterns; TLRs: toll-like receptors; PTPs:
protein tyrosine phosphatases; TFs: transcription factors

complications. Malaria is prevalent among 90 countries, which represent 40% of the world’s population [125] .
Malaria is caused by an intracellular protozoan parasite of the genus Plasmodium, in which five species are
known to infect humans: P. falciparum, P. malariae, P. ovale, P. vivax, and P. knowlesi [126,127] . P. falciparum
causes the most severe clinical form of the infection leading to major morbidity and mortality. Female
Anopheles mosquitoes transmit this disease to humans when releasing sporozoites while taking a blood
meal. These circulate in the blood and invade and mature in hepatocytes. Hepatic forms are released and
invade erythrocytes where merozoites further increase in number and are released and invade other red
blood cells (CDC.org: https://www.cdc.gov/malaria/about/disease.html).

Role of the VE in malaria
The VE plays a major role in host-parasite interactions and the severity of the malarial disease. It has
been shown that P. falciparum antigens are present on the surface of infected erythrocytes and bind to the
[72]
receptors expressed on the VE . After invasion, Plasmodium modulates endothelial function either by
direct adhesion to the EC receptors or by releasing parasite products that can induce EC activation, leading
[73]
to the disruption of the EC barrier . It has also been shown that histones released from merozoites (HeH)
stimulate the production of inflammatory mediators by primary human dermal microvascular endothelial
cells, supporting the pathogenic role of both host- and pathogen-derived histones in P. falciparum caused
malaria [128] .

Malaria caused by P. falciparum is associated with the cytoadherence to endothelial cells through the
parasite ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). P. falciparum-infected RBCs
sequester in blood capillaries through several endothelial cell cytoadherence receptor molecules such
as CXCL1, ICAM1, CD36, and VCAM1 [129] and release exosome-like vesicles to directly communicate
between the parasites [104] . These extracellular vesicles and the other abnormal accumulation of metabolites
play a critical role in the damage of the blood-brain barrier (BBB) in determining the severity of cerebral
malaria (CM) caused by P. falciparum. CM is accompanied by coma, seizures, and focal neurological
deficits, which contribute to a mortality rate of 15%-20% despite therapy [130] . After establishing infection,
Plasmodium export many proteins, including epoxide hydrolases into the erythrocyte, which results in
the alteration of fatty acid composition, leading to perturbed vascular function and sequestration of the
parasite in the VE . Exportation of PfEMP1 mediates the adhesion of infected erythrocytes to VE and
[74]
placental syncytioblasts [131] . In addition, a recent study suggests that brain ECs produce low molecular
weight growth factors, which stimulate the growth of P. falciparum in vitro. These growth factors potentially
[75]
enhance parasite proliferation in erythrocytes in the brain microvasculature .