miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

摘要

miR-155 has been shown to participate in host response to infection and neuroinflammation via negative regulation ofblood-brain barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis ofcerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimentalmodel of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandanchildren with CM were used to examine anti–miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higherparasitemia, survival was significantly improved in miR-155-/- mice versus wild-type littermate mice in ECM. Improved survival wasassociated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of proinflammatorycytokines. Pretreatment with antagomir-155 reduced vascular leak induced by human CM sera in an ex vivo endothelialmicrovessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria viaregulation of endothelial activation, microvascular leak and BBB dysfunction in CM.