title: Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection.
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(+) 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.
  
  
  OBJECTIVE
  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 DENV serotypes is inhibited by therapeutic administration of a genetically modified antibody or a RIG-I receptor agonist that stimulates innate immunity.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Pinto
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Brien
authors.affiliation: MacroGenics, Inc., South San Francisco, California, USA.
authors.forename: Chia-Ying Kao
authors.initials: CY
authors.lastname: Lam
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, USA.
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Pasteur Institute of Rome, Rome, Italy.
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiang
authors.affiliation: Pasteur Institute of Rome, Rome, Italy.
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.affiliation: Sealy Center for Vaccine Development and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Sarathy
authors.affiliation: Sealy Center for Vaccine Development and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Barrett
authors.affiliation: Center for Infectious Disease, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA diamond@borcim.wustl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D019067:Antibody-Dependent Enhancement; D003715:Dengue / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007155:Immunologic Factors / Q000302:isolation & purification* / Q000627:therapeutic use; D051379:Mice
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007155:Immunologic Factors