title: Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria.
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.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.|Department of Medicine, Unit of Anatomy, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Mantel
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Hjelmqvist
authors.affiliation: Department of Medicine, Unit of Anatomy, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0001-7284-3291
authors.initials: M
authors.lastname: Walch
authors.affiliation: Department of Medicine, Unit of Anatomy, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Kharoubi-Hess
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Deepali
authors.initials: D
authors.lastname: Ravel
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Christof
authors.initials: C
authors.lastname: Grüring
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Prasad
authors.initials: P
authors.lastname: Padmanabhan
authors.affiliation: Harvard Catalyst Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Trachtenberg
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Johan
authors.initials: J
authors.lastname: Ankarklev
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.|Wellcome Trust Center for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Brancucci
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
authors.affiliation: Division of Allergy and Infection, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Ionita
authors.initials: I
authors.lastname: Ghiran
authors.affiliation: Harvard Catalyst Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts 02115, USA.|Predicine, Inc., Hayward, California 94545, USA.
authors.forename: Winston P
authors.initials: WP
authors.lastname: Kuo
authors.affiliation: Department of Medicine, Unit of Anatomy, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Luis
authors.initials: L
authors.lastname: Filgueira
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Martinelli
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.|Wellcome Trust Center for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002460:Cell Line; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology* / Q000648:ultrastructure; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000166:cytology; D034743:RNA-Induced Silencing Complex / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex