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 neuroinflammation 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 anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved in miR-155−/− mice versus wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of proinflammatory cytokines. Pretreatment 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.
This study was supported in part by the Canadian Institutes of Health Research (CIHR MOP-13721, MOP-136813 and MOP-115160 and a CIHR Foundation grant to KCK); Canadian Vascular Network Seed Funding and CIHR (MOP-119506 to JEF); Canadian Research Chairs (to KCK, WCL and JEF); and kind donations from the Tesari Foundation and Kim Kertland. Studentship provided by Peterborough KM Hunter Charitable Foundation Graduate Awards and the McCuaig-Throop Bursary (to KRB) and Canadian Vascular Network Scholarships (to HSC and MSN). We thank Dr. Lena Serghides for technical expertise.
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