[en] 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 in miR-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 an ex vivo endothelial 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Barker, Kevin Richard; University of Toronto, Ontario, Canada > Department of Laboratory Medicine and Pathobiology
Lu, Ziyue; Sandra Rotman Centre for Global Health, University Health Network–Toronto General Hospital, and Tropical Disease Unit, Department of Medicine, University of Toronto, Ontario, Canada
Kim, Hani; 2 Sandra Rotman Centre for Global Health, University Health Network–Toronto General Hospital, and Tropical Disease Unit, Department of Medicine, University of Toronto, Ontario, Canada
Zheng, Ying; Department of Bioengineering and Center of Cardiovascular Biology, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
Chen, Junmei; Bloodworks Northwest Research Institute, Seattle, Washington, United States of America
Conroy, Andrea L.; Sandra Rotman Centre for Global Health, University Health Network–Toronto General Hospital, and Tropical Disease Unit, Department of Medicine, University of Toronto, Ontario, Canada
Hawkes, Michael; Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Cheng, Henry S.; Toronto General Research Institute, University Health Network, and Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada,
Njock, Makon-Sébastien ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Fish, Jason E.; Toronto General Research Institute, University Health Network, and Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada
Harlan, John M.; Department of Medicine, University of Washington, Seattle, Washington, United States of America
Lopez, Jose A.; Department of Medicine, University of Washington, Seattle, Washington, United States of America
Liles, W. Conrad; Department of Medicine, University of Washington, Seattle, Washington, United States of America
Kain, Kevin C.; Sandra Rotman Centre for Global Health, University Health Network–Toronto General Hospital, and Tropical Disease Unit, Department of Medicine, University of Toronto, Ontario, Canada,
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