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Cheng et al. Vessel Plus 22020;4:17 I http://dx.doi.org/10.20517/2574-1209.2020.08 Page 5 of 15

decoy strategy as it is capable of inducing both the production of inflammatory cytokines (IL-12, CCL2,
and CCL4) by monocytes after internalisation and transcriptomic changes . Furthermore, as the majority
[51]
of the body’s natural immune response to P. falciparum targets PfEMP1, the secretion of PfEMP1-
containing EVs could possibly work as a smokescreen by attracting neutralising antibodies that protect the
parasite from the immune system [13,51] . EVs can also mediate immunosuppression in mice infected with
+
malaria with EVs from P. berghei-iRBCs able to inhibit CD4 T cell proliferation in response to antigen
presentation. This process seems to be mediated by two potential virulence factors, histamine-releasing
factor and elongation factor 1α (EF-1α). Importantly, this work also showed that mice immunisation with
EVs from P. berghei-iRBCs or recombinant P. berghei-EF-1α resulted in resistance to infection, further
[58]
suggesting the role of EVs in immune-modulation and potential for vaccine development .
Exosome-like vesicles derived from iRBCs have been reported to facilitate communication between iRBCs
and therefore, promoting gametocytogenesis between parasites in vitro via the transfer of a P. falciparum
[59]
protein . This communication is also used to improve parasite survival within the host as well as
transmission to mosquitoes.

Although not specifically studied in an in vitro model of CM, endothelial MVs interacting with T
lymphocytes have been found to assist cell proliferation by inducing cell activation and antigen presentation
[60]
by immune cells . In addition, when MVs from lipopolysaccharide-stimulated monocytes are internalised
by HBECs, they release high levels of MVs (usually a sign of cell activation) and at the same time, display
an increase in trans-endothelial resistance (i.e., tightening of endothelial junctions) which could have a
protective effect on the BBB if occurring in vivo. This suggests that MVs from monocytes, as was shown for
MVs from neutrophils, could trigger contrasting protective and pathogenic responses [61-63] .

In vitro models of malaria are limited in their ability to mirror the pathogenesis of CM and more complex
systems are needed to understand the fine interplay between host cells and EVs during malaria infection.

IN VIVO MODELS OF MALARIA: WHAT DO EXTRACELLULAR VESICLES BRING TO

PATHOGENESIS?
Although there is still debate regarding the usefulness of murine models for studying the pathogenesis
of CM, human studies are limited and often, post-mortem analyses are the only way to explore some
parameters. However, the number of studies that find parallels between human and experimental CM (ECM)
+
[64]
continues to grow. Most recently a study observed that in post-mortem cases of paediatric CM, CD8 T
cells were found within both the vascular lumen as well as the juxtavascular space as was previously shown
in murine CM studies [65,66] . Therefore, animal models can still provide relevant basic scientific knowledge
and allow testing of important hypotheses related to the pathogenesis of the disease [67-71] . For instance,
whole-animal imaging using transgenic fluorescent parasites has demonstrated that sequestration, and
not only accumulation, of iRBCs, does occur in all organs similar to humans [72-74] . In addition, recent
quantitative mapping of mice brains during ECM showed similar numbers compared to human CM despite
the distinct aetiology . However, as for any model, it is not perfect and should be used with caution and
[75]
one should be aware of its limitations before drawing direct conclusions with human disease.
[40]
[76]
Two different Plasmodium species are commonly used in CM models, P. yoelii and P. berghei ,
notably P. berghei ANKA (PbA). During the acute phase of infection, mouse strains that are susceptible
to CM (e.g., CBA/J, C57BL/6, DBA1) display increased levels of plasma MVs similar to that observed in
humans [76-78] . We examined the ATP-binding cassette transporter A1, which modulates the distribution of
[76]
phosphatidylserine to the outer leaflet of the cell plasma membrane at the time of MV production . We
found that mice lacking this ATP-binding cassette had resistance to the malaria-associated neurological