miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria.
miR-155 has been shown to participate in host response to infection and neuro-inflammation via negative regulation of blood-brain-barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis of cerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimental model of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandan children with CM were used to examine an anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved inmiR-155-/-mice vs. wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of pro-inflammatory cytokines. Pre-treatment with antagomir-155 reduced vascular leak induced by human CM sera in anex vivoendothelial microvessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria via regulation of endothelial activation, microvascular leak and BBB dysfunction in CM.
Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.|Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada.
Kevin Richard
KR
Barker
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada.
Ziyue
Z
Lu
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada.
Hani
H
Kim
Department of Bioengineering, University of Washington, Seattle, WA, USA; Center of Cardiovascular Biology, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
Ying
Y
Zheng
Bloodworks Northwest Research Institute, Seattle, WA, USA.
Junmei
J
Chen
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada.
Andrea L
AL
Conroy
Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
Michael
M
Hawkes
Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.|Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada.
Henry S
HS
Cheng
Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada.
Makon-Sébastien
MS
Njock
Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.|Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada.
Jason E
JE
Fish
Department of Medicine, University of Washington, Seattle, WA, USA.
John M
JM
Harlan
Bloodworks Northwest Research Institute, Seattle, WA, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.
Jose A
JA
López
Department of Medicine, University of Washington, Seattle, WA, USA.
W Conrad
WC
Liles
Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.|Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada.
Kevin C
KC
Kain
antagomir; cerebral malaria; microRNAs; microvessels; plasmodium