Image: Human umbilical vein endothelial cell (HUVEC) microvessels perfused with sera from children with cerebral malaria (CM) illustrate greater dextran leak versus sera control, which can be prevented with preincubation with miR-155 antagomir.
miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria. Kevin R Barker, Ziyue Lu, Hani Kim, Ying Zheng, Junmei Chen, Andrea L Conroy, Michael Hawkes, Henry S Cheng, Makon-Sébastien Njock, Jason E Fish, John M Harlan, Jose A López, W Conrad Liles, and Kevin C Kain. Molecular Medicine. 2017 February 2; 23.
Abstract
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.