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Nat Commun. 2016 Oct 10;7:12727. doi: 10.1038/ncomms12727.

Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria.

Author information

1
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
2
Department of Medicine, Unit of Anatomy, University of Fribourg, 1700 Fribourg, Switzerland.
3
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
4
Harvard Catalyst Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Wellcome Trust Center for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.
6
Division of Allergy and Infection, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
7
Predicine, Inc., Hayward, California 94545, USA.
8
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.

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.

PMID:
27721445
PMCID:
PMC5062468
DOI:
10.1038/ncomms12727
[Indexed for MEDLINE]
Free PMC Article

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