Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection

Amelia K. Pinto, James D. Brien, Chia Ying Kao Lam, Syd Johnson, Cindy Chiang, John Hiscott, Vanessa V. Sarathy, Alan D. Barrett, Sujan Shresta, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


With over 3.5 billion people at risk and approximately 390 million human infections per year, dengue virus (DENV) disease strains health care resources worldwide. Previously, we and others established models for DENV pathogenesis in mice that completely lack subunits of the receptors (Ifnar and Ifngr) for type I and type II interferon (IFN) signaling; however, the utility of these models is limited by the pleotropic effect of these cytokines on innate and adaptive immune system development and function. Here, we demonstrate that the specific deletion of Ifnar expression on subsets of murine myeloid cells (LysM Cre+ Ifnarflox/flox [denoted as Ifnarf/f herein]) resulted in enhanced DENV replication in vivo. The administration of subneutralizing amounts of cross-reactive anti-DENV monoclonal antibodies to LysM Cre+ Ifnarf/f mice prior to infection with DENV serotype 2 or 3 resulted in antibody-dependent enhancement (ADE) of infection with many of the characteristics associated with severe DENV disease in humans, including plasma leakage, hypercytokinemia, liver injury, hemoconcentration, and thrombocytopenia. Notably, the pathogenesis of severe DENV-2 or DENV-3 infection in LysM Cre+ Ifnarf/f mice was blocked by pre-or postexposure administration of a bispecific dual-affinity retargeting molecule (DART) or an optimized RIG-I receptor agonist that stimulates innate immune responses. Our findings establish a more immunocompetent animal model of ADE of infection with multiple DENV serotypes in which disease is inhibited by treatment with broad-spectrum antibody derivatives or innate immune stimulatory agents.

Original languageEnglish
Article numbere01316-15
Issue number5
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 Pinto et al.

ASJC Scopus subject areas

  • Microbiology
  • Virology


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