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Cheng et al. Vessel Plus 22020;4:17 I http://dx.doi.org/10.20517/2574-1209.2020.08 Page 3 of 15

Sequestration occurs via the binding of parasite-related ligands, expressed on the surface of iRBCs, to
receptors on the surface of vascular endothelial cells. P. falciparum erythrocyte membrane protein 1
(PfEMP1) is one such molecule expressed on the surface of iRBCs that then binds to a series of endothelial
receptors such as CD36, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion
molecule-1, P-selectin, E-selectin, endothelial protein C receptor or thrombospondin. The expression of
these receptors is further modulated by pro-inflammatory cytokines such as tumour necrosis factor (TNF)
or interferon-gamma (IFN-γ), thereby supporting inflammation as a critical player in the regulation of
sequestration [13,14] .

[15]
Together with iRBCs and nRBCs, platelets also play an important role in CM . Thrombocytopenia is a
hallmark of CM but whether platelet counts can be predictive of lethality in CM is still controversial [16,17] .
Platelets were found in high numbers in vascular lesions of the brain of Malawian children who succumbed
[18]
[19]
to CM and are thought to have contributed to the severity of the disease through clumping , activation
[20]
of endothelial cells or increased sequestration via the transfer of CD36 to brain endothelial cells that are
[21]
otherwise devoid of it . On the other hand, platelets also are thought to have a protective role during CM
by killing intra-erythrocytic parasites [22,23] . Therefore, platelets could have different roles at different stages
[24]
of the disease, i.e., a protective role during the early phase of disease and a pathogenic role when severe .
The BBB is at the centre of the neurovascular lesion occurring in CM although iRBCs do not actively
cross this barrier as seen in other pathogens with brain tropism [25,9] . Post-mortem histopathological brain
studies have demonstrated impairment of the BBB which suggests that the localised sequestration of
iRBCs increases the pressure within microvessels to act on cellular tight junctions, thereby altering the
permeability of the BBB which results in micro-haemorrhages when these junctions rupture. Neurological
sequelae observed in children who have recovered from CM are also suggestive of neuronal damage .
[26]
Neuronal dysfunction is likely an indirect consequence of the sequestration of iRBCs, activation of the
endothelium, alteration of junctional permeability and passage of cytokines, chemokines and other
inflammatory mediators into the perivascular space [27,28] . However, in most cases, it is likely that these
alterations are localised, as symptoms are quickly reversed once parasites have been eliminated. More
recently, Magnetic Resonance Imaging has been successfully used as a non-invasive way to predict fatal
outcomes in paediatric CM, notably in Malawi [29,30] .

As mentioned earlier, crosstalk between vascular cells, including immune and brain parenchyma cells,
via direct contact, soluble mediators and molecules leaking through the BBB, can all contribute to the
neurological syndrome. In addition, subjecting all these cells to various stimuli can lead to the release
of EVs that in turn, target other cells distant from their site of production. Long considered as inert
cellular debris, EVs are now accepted as biological effectors in many infectious and inflammatory diseases
including malaria [31,32] .

EVs represent an ensemble of membrane-bound structures grouped into three main categories: exosomes,
microvesicles, and apoptotic bodies. This nomenclature can vary and the term EVs usually encompasses
subpopulations of vesicles ranging in size from 30 nm to 4 µm, i.e., exosomes produced by membrane
invagination of multivesicular bodies, microvesicles (MVs) released after budding of the plasma membrane,
[33]
or apoptotic bodies that result from blebbing of the plasma membrane of apoptotic cells . It is now clear
that the role of EVs goes far beyond simple structural function to active mediators of important biological
processes for parasitic infections such as immunomodulation, parasite virulence, target cell invasion and
parasite-parasite communication [34,35] .

In malaria infection, two categories of EVs (i.e., exosomes and microvesicles) have been studied the most.
While known in other illnesses for several decades, MVs in malaria patients were first described by our