Abstract
Malaria remains one of the greatest public health challenges worldwide, particularly in sub-Saharan Africa. The clinical outcome of individuals infected with Plasmodium falciparum parasites depends on many factors including host systemic inflammatory responses, parasite sequestration in tissues and vascular dysfunction. Production of pro-inflammatory cytokines and chemokines promotes endothelial activation as well as recruitment and infiltration of inflammatory cells, which in turn triggers further endothelial cell activation and parasite sequestration. Inflammatory responses are triggered in part by bioactive parasite products such as hemozoin and infected red blood cell-derived extracellular vesicles (iRBC-derived EVs). Here we demonstrate that such EVs contain functional miRNA-Argonaute 2 complexes that are derived from the host RBC. Moreover, we show that EVs are efficiently internalized by endothelial cells, where the miRNA-Argonaute 2 complexes modulate target gene expression and barrier properties. Altogether, these findings provide a mechanistic link between EVs and vascular dysfunction during malaria infection.
Highlights
Malaria remains one of the greatest public health challenges worldwide, in sub-Saharan Africa
Results infected red blood cells (iRBCs)-derived extracellular vesicles (EVs) contain a subset of human miRNAs
We have previously developed a protocol for purification of iRBCderived EVs, and we have demonstrated the presence of specific parasite and host proteins in purified EVs, including human Ago[2]
Summary
Malaria remains one of the greatest public health challenges worldwide, in sub-Saharan Africa. We show that EVs are efficiently internalized by endothelial cells, where the miRNA-Argonaute 2 complexes modulate target gene expression and barrier properties These findings provide a mechanistic link between EVs and vascular dysfunction during malaria infection. The pathology of P. falciparum malaria is related to the capability of parasite-infected red blood cells (iRBCs) to sequester in deep tissues by adherence to the microvasculature. For this purpose the parasite expresses a variant surface antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1). Release of membranous material in the form of extracellular vesicles (EVs) from iRBCs during parasite development has initially been described in the rodent malaria model and more recently in P. falciparum[10,11,12,13]. The latter can occur through a variety of reported mechanisms including decreased mRNA stability due to deadenylation and uncapping, or via direct inhibition of translation[21]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.