Gamma Interferon (IFN-) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-/ Receptor-Deficient Mice

We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-/R and-R) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-R alone and virtually nomice lacking the IFN-/R alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-/R, signaling through the IFN-R confers approximately 140-fold greater resis-tance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paral-ysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-R signaling by 2 days after infection, coincident with elevated levels of IFN- in the spleen and serum. By 4 days after infection, IFN-R signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-R, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN- from CD8 T cells. These results demonstrate the roles of IFN-R signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8 T cells in preventing DENV-induced CNS disease. The four serotypes of dengue virus (DENV1 to-4) belong to theFlaviviridae family, which also includes West Nile virus (WNV), St. Louis encephalitis virus (SLEV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV). More than 2.5 billio