title: 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.
abstract: 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.
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Supranee
authors: S
authors: Phanthanawiboon
authors: Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors: Kriengsak
authors: K
authors: Limkittikul
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Yusuke
authors: Y
authors: Sakai
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Nobuyuki
authors: N
authors: Takakura
authors: Department of Virology I, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan.
authors: Masayuki
authors: M
authors: Saijo
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Takeshi
authors: T
authors: Kurosu
mesh_terms: D000208:Acute Disease; D042682:Angiopoietins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015415:Biomarkers; D002199:Capillary Permeability; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D003715:Dengue / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D003716:Dengue Virus; D004195:Disease Models, Animal; D015870:Gene Expression; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D051379:Mice; D018345:Mice, Knockout; D042787:Receptor, TIE-2 / Q000378:metabolism*; D017471:Receptors, Interferon / Q000172:deficiency*; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
chemical_list: D042682:Angiopoietins; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D042787:Receptor, TIE-2