IRF7 deficiency in myeloid cells results in increased disease severity and death during alphavirus encephalomyelitis despite intact expression of type I interferons.

Abstract

Alphaviruses are arthropod-borne pathogens that cause immune-mediated encephalomyelitis. The prototypic alphavirus, Sindbis virus (SINV), primarily infects neurons in mice, resulting in neurologic disease involving both the brain and spinal cord. Interferon (IFN) regulatory factor (IRF) 7-deficient mice (Irf7^-/-) rapidly succumb to SINV infection with extensive immunopathology while wildtype mice experience only mild disease and recover. IRF7 is widely recognized to be the main transcription factor required for the amplification of type I IFN, specifically IFNα, as Irf7^-/- mice do not produce IFNα but do express IFNβ. However, based on the current experimental evidence, it is not clear if the severe outcome of SINV infection in Irf7^-/- mice is due to the absence of IFNα or heretofore unappreciated noncanonical actions of IRF7. In this study, we demonstrate that the administration of IFNα to Irf7^-/- mice early in infection restricted SINV replication and largely rescued the animals from severe disease and mortality but did not alter the nature of CNS inflammation. Further, Cre-Lox-mediated deletion of Irf7 in myeloid cells (Irf7^fl/flLyz2-cre mice) resulted in severe disease and lethality despite significantly higher peak levels of IFNα than WT animals, suggesting that the lethal phenotype of Irf7^-/- mice was attributed to the myeloid cell-specific loss of IRF7 and not to the loss of IFNα production. Both Irf7^-/- and Irf7^fl/flLyz2-cre mice had increased levels of monocytes infiltrating into the brain compared to WT, indicating a potential role for IRF7 in the trafficking and activation of myeloid cells. Therefore, while IFNα supplementation may contribute to reducing disease severity by restricting virus replication, disease was ultimately exacerbated by the increased infiltration of inflammatory myeloid cells in Irf7^-/- mice.