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.

Sequence diversity of dengue virus type 2 in brain and thymus of infected interferon receptor ko mice: implications for dengue virulence

“…These virulent DENVs are largely classified into two groups, one consisting of viruses that lead to acute lethal infection and another consisting of viruses that cause late death at about day 20 post-infection (p.i.) [24]. Most virulent DENVs belong to the latter group.…”

“…Since the peak of viral production previously was shown to occur at around 5–6 days p.i. in an acute systemic infection model [24], we determined the levels of vRNA in each organ at day 6 p.i. for IFN-α/β/γR/FcγRIIB KO mice infected intraperitoneally with DV2P04/08.…”

“…While wild-type strains of mice do not show DHF-like symptoms upon DENV infection, recent work showed that, AG129 mice, which lack (IFN)-α/β and –γ receptors, can serve as a host for a model of severe dengue [20–23]. However, most DENV isolates do not induce DHF-like symptoms even in these knock out (KO) mice; only a subset of DENV isolates provide lethal infection in this background [24]. In the present study, we studied the infection dynamics of the DV2P04/08 clinical isolate, which causes lethal infection but exhibits slow disease progression in IFN-α/β/γR KO mice.…”

Synergistic Effect of TNF-α and Dengue Virus Infection on Adhesion Molecule Reorganization in Human Endothelial Cells

“…TNF-a, IL-6, and MCP-1 are triggered by dengue virus infection. Treatment with anti-TNF-a antibody also suppressed IL-6, MCP-1, and IFN-a levels, suggesting that severe vascular leakage is triggered by TNF-a (29).…”

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure

“…Viral infection and liver damage is often exacerbated through cytokine storm and immune dysregulation (39)(40)(41). Having shown that the IFN status of the immune compartment is critical for controlling generalized infections and liver damage, we sought to assess whether abnormal cytokine levels were an additional component in the liver disease observed in IFN-␣␤␥R Ϫ/Ϫ mice.…”