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Molecular Medicine

, Volume 23, Issue 1, pp 24–33 | Cite as

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
  • Kevin C. Kain
Research Article

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.

Notes

Acknowledgments

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.

Supplementary material

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© The Author(s) 2017

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Authors and Affiliations

  • Kevin R. Barker
    • 1
    • 2
  • Ziyue Lu
    • 2
  • Hani Kim
    • 2
  • Ying Zheng
    • 3
  • Junmei Chen
    • 4
  • Andrea L. Conroy
    • 2
  • Michael Hawkes
    • 5
  • Henry S. Cheng
    • 1
    • 6
  • Makon-Sébastien Njock
    • 6
  • Jason E. Fish
    • 1
    • 6
  • John M. Harlan
    • 7
  • Jose A. López
    • 4
    • 7
  • W. Conrad Liles
    • 7
  • Kevin C. Kain
    • 1
    • 2
  1. 1.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  2. 2.SAR Laboratories, Sandra Rotman Centre for Global Health, MaRS Centre, University Health Network-Toronto General Hospital and Tropical Disease Unit, Department of MedicineUniversity of TorontoTorontoCanada
  3. 3.Department of Bioengineering and Center of Cardiovascular Biology, Institute of Stem Cell and Regenerative MedicineUniversity of WashingtonSeattleUSA
  4. 4.Bloodworks Northwest Research InstituteSeattleUSA
  5. 5.Division of Infectious Diseases, Department of PediatricsUniversity of AlbertaEdmontonCanada
  6. 6.Toronto General Research InstituteUniversity Health Network, and Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular ResearchTorontoCanada
  7. 7.Department of MedicineUniversity of WashingtonSeattleUSA

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