Inhibition of Megakaryocyte Development in the Bone Marrow Underlies Dengue Virus-Induced Thrombocytopenia in Humanized Mice
Aishwarya Sridharana b, Qingfeng Chena c, Kin Fai Tangd, Eng Eong Ooia d, Martin Lloyd Hibberde, Jianzhu Chena f
- aInterdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore
- bSingapore-MIT Alliance, Singapore
- cInfrastructure, Technology and Translational Division, Institute of Molecular and Cell Biology, ASTAR, Singapore
- dDuke-NUS Graduate Medical School, Singapore
- eGenome Institute of Singapore, Singapore
- fKoch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Abstract
A characteristic clinical feature of dengue virus infection is thrombocytopenia, though its underlying mechanism is not definitively determined. By adoptive transfer of human CD34(+) fetal liver cells into immunodeficient mice, we have constructed humanized mice with significant levels of human platelets, monocytes/macrophages, and hepatocytes. Infection of these mice with both lab-adapted and clinical strains of dengue virus induces characteristic human hematological changes, including transient leukopenia and thrombocytopenia. We show that the specific depletion of human platelets is not mediated by antibodies in the periphery or reduced production of human thrombopoietin in the liver but reduction of human megakaryocytes and megakaryocyte progenitors in the bone marrow of the infected mice. These findings identify inhibition of platelet production in the bone marrow as a key mechanism underlying dengue-induced thrombocytopenia and suggest the utility of the improved humanized mouse model in studying dengue virus infection and pathogenesis in a human cell context.
TL;DRInhibition of platelet production in the bone marrow is identified as a key mechanism underlying dengue-induced thrombocytopenia and the utility of the improved humanized mouse model is suggested in studying d Dengue virus infection and pathogenesis in a human cell context. (Semantic Scholar)