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 Sarathy, Alan Barrett, Sujan Shresta, Michael S. Diamond

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 (US)
Article numbere01316-15
JournalmBio
Volume6
Issue number5
DOIs
StatePublished - 2015

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Dengue Virus
Virus Diseases
Antibodies
Antibody-Dependent Enhancement
Severe Dengue
Therapeutics
Infection
Interferon Type I
Health Resources
Myeloid Cells
Virus Replication
Innate Immunity
Thrombocytopenia
Interferon-gamma
Immune System
Animal Models
Monoclonal Antibodies
Cytokines
Delivery of Health Care
Liver

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Pinto, A. K., Brien, J. D., Lam, C. Y. K., Johnson, S., Chiang, C., Hiscott, J., ... Diamond, M. S. (2015). Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection. mBio, 6(5), [e01316-15]. https://doi.org/10.1128/mBio.01316-15

Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection. / Pinto, Amelia K.; Brien, James D.; Lam, Chia Ying Kao; Johnson, Syd; Chiang, Cindy; Hiscott, John; Sarathy, Vanessa; Barrett, Alan; Shresta, Sujan; Diamond, Michael S.

In: mBio, Vol. 6, No. 5, e01316-15, 2015.

Research output: Contribution to journalArticle

Pinto, AK, Brien, JD, Lam, CYK, Johnson, S, Chiang, C, Hiscott, J, Sarathy, V, Barrett, A, Shresta, S & Diamond, MS 2015, 'Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection', mBio, vol. 6, no. 5, e01316-15. https://doi.org/10.1128/mBio.01316-15
Pinto, Amelia K. ; Brien, James D. ; Lam, Chia Ying Kao ; Johnson, Syd ; Chiang, Cindy ; Hiscott, John ; Sarathy, Vanessa ; Barrett, Alan ; Shresta, Sujan ; Diamond, Michael S. / Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection. In: mBio. 2015 ; Vol. 6, No. 5.
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