Sendai Virus Pathogenesis in Mice Is Prevented by Ifit2 and Exacerbated by Interferon

Th e type I/III interferon (IFN) system has major roles in regulating viral pathogenesis, usually ameliorating pathogenesis by impairing virus replication through the antiviral actions of one or more IFN-induced proteins. Ifit2 is one such protein which can be induced by IFN or virus infection, and it is responsible for protecting mice from neuropathogenesis caused by vesicular stomatitis virus. Here, we show that Ifit2 also protects mice from pathogenesis caused by the respirovirus Sendai virus (SeV). Mice lacking Ifit2 (Ifit2(-/-)) suffered severe weight loss and succumbed to intranasal infection with SeV strain 52 at a dose that killed only a few wild-type mice. Viral RNA was detectable only in lungs, and SeV titers were higher in Ifit2(-/-) mice than in wildtype mice. Similar infiltration of immune cells was found in the lungs of both mouse lines, corresponding to similar levels of many induced cytokines and chemokines. In contrast, IFN-beta and IFN-lambda(3) expression were considerably higher in the lungs of Ifit2(-/-) mice. Surprisingly, type I IFN receptor knockout (IFNAR(-/-)) mice were less susceptible to SeV than Ifit2(-/-) mice, although their pulmonary virus titers were similarly high. To test the intriguing possibility that type I IFN action enhances pathogenesis in the context of elevated SeV replication in lungs, we generated Ifit2/IFNAR(-/-) double knockout mice. These mice were less susceptible to SeV than Ifit2(-/-) mice, although viral titers in their lungs were even higher. Our results indicate that high SeV replication in the lungs of infected Ifit2(-/-) mice cooperates with elevated IFN-beta induction to cause disease. IMPORTANCE The IFN system is an innate defense against virus infections. It is triggered quickly in infected cells, which then secrete IFN. Via their cell surface receptors on surrounding cells, they induce transcription of numerous IFN-stimulated genes (ISG), which in turn protect these cells by inhibiting virus life cycles. Hence, IFNs are commonly considered beneficial during virus infections. Here, we report two key findings. First, lack of a single ISG in mice, Ifit2, resulted in high mortality after SeV infection of the respiratory tract, following higher virus loads and higher IFN production in Ifit2(-/-) lungs. Second, mortality of Ifit2(-/-) mice was reduced when mice also lacked the type I IFN receptor, while SeV loads in lungs still were high. This indicates that type I IFN exacerbates pathogenesis in the SeV model, and that limitation of both viral replication and IFN production is needed for effective prevention of disease.