The mRNA content of plasma extracellular vesicles provides a window into molecular processes in the brain during cerebral malaria.

The impact of cerebral malaria on the transcriptional profiles of cerebral tissues is difficult to study using noninvasive approaches. We isolated plasma extracellular vesicles (EVs) from patients with cerebral malaria and community controls and sequenced their mRNA content. Deconvolution analysis revealed that EVs from cerebral malaria are enriched in transcripts of brain origin. We ordered the patients with cerebral malaria based on their EV-transcriptional profiles from cross-sectionally collected samples and inferred disease trajectory while using healthy community controls as a starting point. We found that neuronal transcripts in plasma EVs decreased with disease trajectory, whereas transcripts from glial, endothelial, and immune cells increased. Disease trajectory correlated positively with severity indicators like death and was associated with increased VEGFA-VEGFR and glutamatergic signaling, as well as platelet and neutrophil activation. These data suggest that brain tissue responses in cerebral malaria can be studied noninvasively using EVs circulating in peripheral blood.