ETS-guided iPSC-endothelial models recapitulate malaria pathogenesis.

The sequestration of the malaria parasite in the microvasculature is a major driver of severe malaria, but the human specificity of Plasmodium falciparum has challenged our understanding of this key pathogenic process. Advances in induced pluripotent stem cell (iPSC) technologies offer unique opportunities to study parasite-host interactions in a well-defined environment. However, endothelial iPSC differentiation methods often result in cells with mixed epithelial identity. Here, we have generated an iPSC line with inducible and simultaneous expression of ETS transcription factors (ETV2, FLI1, ERG), resulting in cells with improved endothelial identity and strong barrier function (ETS-iBMEC). Parasite-infected red blood cells and neutrophils display high binding to ETS-iBMEC. Exposure to parasite products caused transcriptional changes in metabolic and splicing genes, and key endothelial barrier and angiogenic pathways. Our study confirms the role of the angiopoietin-Tie2 axis in parasite-mediated barrier disruption and highlights the importance of new pathways, including VEGF-Notch signalling. Our novel iPSC-based approach represents a new in vitro platform to study the pathogenesis of human vascular infections.