Interferon Regulatory Factor 7-mediated induction of interferon-α is required for survival from alphavirus encephalomyelitis

Abstract

Abstract Alphaviruses are a group of arthropod-borne viruses that have the capacity to cause encephalomyelitis, which is inflammation of the brain and spinal cord due to the immune response to viral infection, and can result in fever, headache, and neurologic disease such as cognitive impairment, seizures, ataxia, and paralysis. Neurons are the primary target cells of Sindbis virus (SINV), the prototypic alphavirus; however, due to the indispensable nature of neurons, mechanisms of viral clearance from the central nervous system (CNS) during recovery cannot depend on immune-mediated killing of infected neurons and is therefore specialized. We have previously shown that interferon (IFN) regulatory factor (IRF) 7, a transcription factor important for amplification of type I IFN (mainly IFNα), is required for survival from infection with SINV. Mice deficient in IRF7 succumb to infection – despite local production of IFNβ – while wild type (WT) mice recover. Treatment of Irf7−/−mice with IFNα rescues the WT phenotype, suggesting that IRF7-mediated induction of IFNα and subsequent downstream signaling is required for survival from SINV infection. Additionally, Ifnb−/−mice do not phenocopy Irf7−/−mice, further suggesting that IFNα is required for survival while IFNβ is dispensable despite usage of the same receptor. Interestingly, Ifnb−/−mice have similar viral titers to Irf7−/−mice, implying that the protective effects of IFNα are independent from restriction of viral replication. These findings show subtype-specific differences in protection by type I IFN and can inform treatment options for alphavirus-induced encephalomyelitis. These works have been funded by the U.S. National Institutes of Health (R01 NS087539 and T32 AI007417).