DENV is a globally important human pathogen that causes disease ranging from mild to severe and life threatening. The disease is thought to be immune-mediated where the response to infection leads to damage to the host. Unfortunately, DENV does not replicate well or cause symptoms reflective of human disease in mice, unless the mice are immunodeficient such as in the AG129 interferon (IFN)-receptor knockout mouse. This is poses a problem for investigations of the IFN response in vivo. DENV does, however replicate in the brain and cause symptoms of neurovirulence such as loss of hind limb movement in immunocompetent mice. Here, we assessed the induction of type I IFN (IFN-β), IFN-stimulated genes (ISGs) and T lymphocyte infiltration following DENV infection in vivo.
3-4 weeks old WT C57BL/6 mice were infected intracranially (i.c.) with DENV-2 and mice monitored for reduced motor function and body weight loss. At 1, 3, and 6 days post infection (dpi) or end stage disease (6-8 dpi) mice were euthanized and their brains harvested for RNA extraction and qRT-PCR.
DENV infection of mice induced disease by 6-8 days. Mice induced body weight loss in all DENV-infected mice. The presence of neurovirulence symptoms was associated with increased DENV RNA levels. IFN-β was induced at 3-6 dpi but declined by the onset of end stage disease. The ISGs viperin, IFIT1, OAS-1, IRF7, If27i2a, and CXCL10 were significantly induced 3-6 dpi and remain elevated until end stage of disease. Infection was associated with increased CD8 but not CD4 mRNA, suggesting CD8 but not CD4 T-cell infiltration at 6 dpi and at end stage of disease.
Outcomes of our study demonstrate that DENV-2 infection of the brain in mice induces IFN-β, ISGs expression and CD8+ T cell infiltration. Further analysis will define T-cell infiltration histologically; investigate the cell types responsible for expression of ISGs and DENV infection and the role of the ISG viperin as an anti-DENV response in the brain.