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

• Main Authors: Kevin R. Barker (Author), Ziyue Lu (Author), Hani Kim (Author), Ying Zheng (Author), Junmei Chen (Author), Andrea L. Conroy (Author), Michael Hawkes (Author), Henry S. Cheng (Author), Makon-Sébastien Njock (Author), Jason E. Fish (Author), John M. Harlan (Author), Jose A. López (Author), W. Conrad Liles (Author), Kevin C. Kain (Author)
• Format: Book
• Published: BMC, 2017-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.2119/molmed.2016.00139
1076-1551
1528-3658