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

We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-alpha/beta R and -gamma R) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-gamma R alone and virtually no mice lacking the IFN-alpha/beta R alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-alpha/beta R, signaling through the IFN-gamma R confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. 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-gamma R signaling by 2 days after infection, coincident with elevated levels of IFN-gamma in the spleen and serum. By 4 days after infection, IFN-gamma R signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-gamma R, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-gamma from CD8(+) T cells. These results demonstrate the roles of IFN-gamma 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.