Academic Journal
Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection
| العنوان: | Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection |
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| المؤلفون: | Pinto, Amelia K., Brien, James D., Lam, Chia-Ying Kao, Johnson, Syd, Chiang, Cindy, Hiscott, John, Sarathy, Vanessa V., Barrett, Alan D., Shresta, Sujan, Diamond, Michael S. |
| المساهمون: | Denison, Mark R. |
| المصدر: | mBio ; volume 6, issue 5 ; ISSN 2161-2129 2150-7511 |
| بيانات النشر: | American Society for Microbiology |
| سنة النشر: | 2015 |
| الوصف: | 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 + 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 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. 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1128/mbio.01316-15 |
| DOI: | 10.1128/mBio.01316-15 |
| الاتاحة: | http://dx.doi.org/10.1128/mbio.01316-15 https://journals.asm.org/doi/pdf/10.1128/mBio.01316-15 |
| Rights: | http://creativecommons.org/licenses/by-nc-sa/3.0/ ; https://journals.asm.org/non-commercial-tdm-license |
| رقم الانضمام: | edsbas.4445B475 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1128/mbio.01316-15 |
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