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and miR-467a were all elevated in brain tissue from CM mice when compared to non-infected or non-
CM infected mice [126] . This difference in miRNA profiles suggests that miRNA present in circulation could
have different functions from those present in tissues. Further investigation to verify the potential of these
EVs derived miRNA as biomarkers for the cerebral syndrome using both experimental models and clinical
samples will be necessary.

CONCLUSION
In vivo and ex vivo studies point towards a role for EVs in the modulation of disease and the host response.
No study has looked at the behaviour of EVs in situ however. Rather than passively transferred EVs, animal
models utilising both transgenic parasites and transgenic host cells expressing tags that can be traced,
combined with high-resolution imaging in the animal, will allow us to truly understand the complex
involvement of EVs with their target cells. For instance, recent work used high-resolution microscopy to
visualise circulating EVs in zebrafish embryos using a tissue-specific expression of genetically encoded
markers of EVs. This approach will allow us to not only decipher the role of EVs in physiology including
cargo delivery but also, to assess the effects of disease or treatment on EVs release and function [127] .

In addition, although evidence confirming the importance of EVs as a source of biomarkers are scattered,
they also highlight a number of questions and unsolved problems. Indeed, most of the work performed
so far still lack validation steps and clinical studies remain scarce. These limitations are such that most
studies remain mainly descriptive and hamper the process of biomarker validation and implementation
into clinical practice. In-depth investigations should also be carried out to understand the mechanisms of
protein and miRNA packaging into EVs, as well as the signals involved in cell targeting. Deciphering these
processes will contribute to the selection of highly specific biomarkers for larger validation studies. While
biomarker studies applied to severe malaria and EVs are still in their infancy, there is hope for this field to
provide novel strategies to fight severe malaria in the future.

DECLARATIONS
Authors’ contributions
Conceived and designed the review: Cheng IS, Sealy BC, Tiberti N, Combes V
Made equal contribution to the writing of the sections: Cheng IS, Sealy BC
Provided feedback for manuscript revision: Cheng IS, Sealy BC
Read and approved the final manuscript: Cheng IS, Sealy BC, Tiberti N, Combes V

Availability of data and materials
Not applicable.

Financial support and sponsorship
Combes V was supported by the University of Technology, Faculty of Science grant. Cheng IS and Sealy
BC were supported by the Australian Government Research Training Program Stipend. Tiberti N was
supported by the Italian Ministry of Health “Fondi Ricerca Corrente - Linea 1 Progetto 3” to IRCCS. Sacro
Cuore Don Calabria Hospital.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.