Cytoadhesion ofPlasmodium falciparum-infected red blood cells changes the expression of cytokine-, histone- and antiviral protein-encoding genes in brain endothelial cells

Abstract

Introduction: Malaria remains a significant global health problem, particularly due to the human malaria parasitePlasmodium falciparum, which is responsible for most fatal infections. Infected red blood cells (iRBCs) evade spleen clearance by adhering to endothelial cells (ECs), triggering capillary blockage, inflammatory cytokine release, endothelial dysfunction, and altered vascular permeability, prompting an endothelial transcriptional response. Methods: The iRBCIT4var04/HBEC-5i model, where iRBCs present IT4var04 (VAR2CSA) on their surface was employed to analyse the effects of iRBC binding on ECs. We used this model to investigate how cytoadhesion of iRBCs to ECs influences their expression profile depending on the temperature (37 degrees celsius vs 40 degrees celsius). Results: Binding of non-infected RBCs (niRBCs) and fever alone significantly changes expression of hundreds of genes in ECs. Comparing the expression profile of HBEC-5i cultured either in the presence of iRBCs or in the presence of niRBCs, genes encoding proteins assigned to the GO terms immune response, nucleosome assembly, NF-kappa B signaling, angiogenesis, and antiviral immune response/interferon-alpha/beta signaling pathway were significantly up-regulated. If the cultivation temperature is increased from 37 degrees celsius to 40 degrees celsius, which simulates fever, a further significant increase in expression can be observed for most regulated genes, especially for genes coding for cytokines and proteins involved in angiogenesis. Conclusion: The presence of iRBCs leads to the stimulation of ECs, activating several immunological signaling pathways and affecting antiviral (-parasitic) mechanisms and angiogenesis. Furthermore, to our knowledge, the induction of the interferon-alpha/beta signaling pathway in ECs in response to iRBCs has been described for the first time.