Acute Systemic Infection with Dengue Virus Leads to Vascular Leakage and Death through Tumor Necrosis Factor-α and Tie2/Angiopoietin Signaling in Mice Lacking Type I and II Interferon Receptors

• Published in: PloS one Vol. 11; no. 2; p. e0148564
• Main Authors: Phanthanawiboon, Supranee, Limkittikul, Kriengsak, Sakai, Yusuke, Takakura, Nobuyuki, Saijo, Masayuki, Kurosu, Takeshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.02.2016; Public Library of Science (PLoS)
• Subjects: Acute Disease; Angiopoietin; Angiopoietins - metabolism; Angiopoietins - pharmacology; Animal models; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - pharmacology; Biology and Life Sciences; Biomarkers; Blood vessels; Capillary Permeability; Cytokines - blood; Cytokines - genetics; Cytokines - metabolism; Dengue; Dengue - genetics; Dengue - metabolism; Dengue - mortality; Dengue - virology; Dengue fever; Dengue hemorrhagic fever; Dengue Virus; Disease Models, Animal; Disseminated infection; Flavivirus; Gene Expression; Hemorrhage; Infections; Infectious diseases; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Interferon; Interferon receptors; Interleukin 6; Kidneys; Laboratory animals; Leakage; Liver; Liver - metabolism; Liver - pathology; Liver Function Tests; Medical research; Medicine and Health Sciences; Mice; Mice, Knockout; Monocyte chemoattractant protein 1; mRNA; Necrosis; Neutralizing; Pathogenesis; Proteins; Receptor, TIE-2 - metabolism; Receptors; Receptors, Interferon - deficiency; Research and Analysis Methods; Rodents; Signal Transduction; Signaling; Small intestine; Survival; Systemic diseases; Thrombocytopenia - etiology; Tropical diseases; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vaccines; Vector-borne diseases; Veterinary medicine; Viral diseases; Viral Load; Virology; Viruses; West Nile virus; α-Interferon; γ-Interferon; Thailand; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148564

Severe dengue is caused by host responses to viral infection, but the pathogenesis remains unknown. This is, in part, due to the lack of suitable animal models. Here, we report a non-mouse-adapted low-passage DENV-3 clinical isolate, DV3P12/08, derived from recently infected patients. DV3P12/08 caused a lethal systemic infection in type I and II IFN receptor KO mice (IFN-α/β/γR KO mice), which have the C57/BL6 background. Infection with DV3P12/08 induced a cytokine storm, resulting in severe vascular leakage (mainly in the liver, kidney and intestine) and organ damage, leading to extensive hemorrhage and rapid death. DV3P12/08 infection triggered the release of large amounts of TNF-α, IL-6, and MCP-1. Treatment with a neutralizing anti-TNF-α antibody (Ab) extended survival and reduced liver damage without affecting virus production. Anti-IL-6 neutralizing Ab partly prolonged mouse survival. The anti-TNF-α Ab suppressed IL-6, MCP-1, and IFN-γ levels, suggesting that the severe response to infection was triggered by TNF-α. High levels of TNF-α mRNA were expressed in the liver and kidneys, but not in the small intestine, of infected mice. Conversely, high levels of IL-6 mRNA were expressed in the intestine. Importantly, treatment with Angiopoietin-1, which is known to stabilize blood vessels, prolonged the survival of DV3P12/08-infected mice. Taken together, the results suggest that an increased level of TNF-α together with concomitant upregulation of Tie2/Angiopoietin signaling have critical roles in severe dengue infection.