Plasmodium falciparum derived extracellular vesicles reprogram host MAP kinase signalling cascade to promote cytoadherence

Severe malaria pathogenesis, caused by Plasmodiumfalciparum, is linked to cytoadherence, during which parasitized RBCs bind to host endothelial receptors, causing microvascular obstruction. Extracellular vesicles released by P.falciparum-infected RBCs (pEVs) are found in higher numbers in the plasma of severe malaria patients, yet their role in cytoadherence remains unexplored. We investigated how pEVs from virulent (FCR3) and non-virulent (3D7A) parasite strains modulate host cell signalling cascade to guide parasite-host cell interactions. Here, we show that FCR3-EVs enhance the cytoadherence of both FCR3 and 3D7A by activating the MAP kinase pathway through p-ERK and downstream transcription factors, c-fos and c-jun. This resulted in upregulation of ICAM-1 and CD36, which promoted parasite binding with host cells. Moreover, pharmacological blockade of host cellular signalling responses abrogated cytoadherence, thereby defining a clear relationship between host cell signalling responses and cytoadhesion. Further, this modulation is due to human derived miRNAs in the pEVs that target phosphatase PTPRR; a negative regulator of MAP kinase leading to accumulation of pERK. However, 3D7A-EVs differ from FCR3-EVs as they neither activated c-fos and c-jun nor enriched miRNAs against PTPRR in cells. Therefore, our study provides new insights into the molecular mechanism underlying EV mediated parasite-host communication.