Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice

Jonathan Cox, Javier Mota, Soila Sukupolvi-Petty, Michael S. Diamond, Rebeca Rico-Hesse

    Research output: Contribution to journalArticlepeer-review

    113 Scopus citations

    Abstract

    Dengue viruses (DENV) are transmitted to humans by the bite of Aedes aegypti or Aedes albopictus mosquitoes, with millions of infections annually in over 100 countries. The diseases they produce, which occur exclusively in humans, are dengue fever (DF) and dengue hemorrhagic fever (DHF). We previously developed a humanized mouse model of DF in which mice transplanted with human hematopoietic stem cells produced signs of DENV disease after injection with low-passage, wild-type isolates. Using these mice, but now allowing infected A. aegypti to transmit dengue virus during feeding, we observed signs of more severe disease (higher and more sustained viremia, erythema, and thrombocytopenia). Infected mice mounted innate (gamma interferon [IFN-γ] and soluble interleukin 2 receptor alpha [sIL-2Rα]) and adaptive (anti-DENV antibodies) immune responses that failed to clear viremia until day 56, while a mosquito bite alone induced strong immunomodulators (tumor necrosis factor alpha [TNF-α], IL-4, and IL-10) and thrombocytopenia. This is the first animal model that allows an evaluation of human immunity to DENV infection after mosquito inoculation.

    Original languageEnglish (US)
    Pages (from-to)7637-7649
    Number of pages13
    JournalJournal of virology
    Volume86
    Issue number14
    DOIs
    StatePublished - Jul 2012

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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