title: The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease.
abstract: Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD₅₀) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human "severe dengue" cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice.
authors: Grupo de Investigaciones en Enfermedades Tropicales, Departmento de Ciéncias Básicas Médicas, Universidad del Norte, Barranquilla, Colombia. afalconar@uninorte.edu.co
authors: Andrew K I
authors: AK
authors: Falconar
authors: Fernando
authors: F
authors: Martinez
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009102:Multiple Organ Failure / Q000276:immunology* / Q000821:virology*; D009928:Organ Specificity / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000302:isolation & purification; D014771:Virion / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000956:Antigens, Viral; C079340:NS1 protein, Dengue virus type 2; D017361:Viral Nonstructural Proteins