Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection

被引:44
|
作者
Pinto, Amelia K. [1 ]
Brien, James D. [1 ]
Lam, Chia-Ying Kao [5 ]
Johnson, Syd [6 ]
Chiang, Cindy [7 ]
Hiscott, John [7 ]
Sarathy, Vanessa V. [8 ,9 ]
Barrett, Alan D. [8 ,9 ]
Shresta, Sujan [10 ]
Diamond, Michael S. [1 ,2 ,3 ,4 ]
机构
[1] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA
[5] MaeroGenics Inc, San Francisco, CA USA
[6] MaeroGenics Inc, Rockville, MD USA
[7] Inst Pasteur, Rome, Italy
[8] Univ Texas Med Branch, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA
[9] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA
[10] La Jolla Inst Allercrie & Immunol, Ctr Infect Dis, La Jolla, CA USA
来源
MBIO | 2015年 / 6卷 / 05期
关键词
PROTEIN DOMAIN-III; HEMORRHAGIC-FEVER; MICE DEFICIENT; NEUTRALIZATION; VACCINE; CELLS; INTERFERONS; DISEASE; DETERMINANTS; PATHOGENESIS;
D O I
10.1128/mBio.01316-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 1 and type 11 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(+) Ifnar(flox/flox) [denoted as Ifnar(f/f) herein]) resulted in enhanced DENV replication in vivo. The administration of subneutralizing amounts of cross-reactive anti-DENV monoclonal antibodies to LysM Cre(+) Ifnar(f/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(+) Ifnar(f/f) mice was blocked by pre- or postex-posure administration of a bispecific dual-affinity retargeting molecule (DART) or an optimized RIG-1 receptor agonist that stimulates innate immune responses. Our findings establish a more immunocompetent animal model of ADE of infection with multiple DENY serotypes in which disease is inhibited by treatment with broad-spectrum antibody derivatives or innate immune stimulatory agents. IMPORTANCE Although dengue virus (DENV) infects hundreds of millions of people annually and results in morbidity and mortality on a global scale, there are no approved antiviral treatments or vaccines. Part of the difficulty in evaluating therapeutic candidates is the lack of small animal models that are permissive to DENV and recapitulate the clinical features of severe human disease. Using animals lacking the type I interferon receptor only on myeloid cell subsets, we developed a more immunocompetent mouse model of severe DENV infection with characteristics of the human disease, including vascular leakage, hemoconcentration, thrombocytopenia, and liver injury. Using this model, we demonstrate that pathogenesis by two different DENY seroes is inhibited by therapeutic administration of a genetically modified antibody or a RIG-I receptor agonist that stimulates innate immunity.
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页数:13
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