Type I interferon locus evolved to expand Ifna genes and to differentially regulate cytokine production to combat diverse pathogenic viruses 4629

Abstract Description Mammals encode many type I interferons (IFN-I), Ifnb1 and multiple Ifna genes. Why Ifna, but not Ifnb1, has expanded and if this expansion correlates with protection are unclear. To test individual and collective contribution of IFN-I for viral resistance, we made IFN-I knockout mice. Lack of many Ifna or of Ifna4 did not break resistance to ectromelia virus (ECTV) and to West Nile virus (WNV) while Ifnb1 gene silencing caused susceptibility to these viruses in C57BL/6 (B6) mice. Mice lacking both IFN-β and IFN-α4 were more susceptible to ECTV and WNV than Ifnb1-/- mice. Ifna-/- mice (lack all Ifna genes) were mildly susceptible to ECTV but highly susceptible to WNV. IFN-β was the predominant bioactive subtype in the serum of ECTV-infected B6 mice while IFN-α was the predominant subtype in WNV-infected B6 mice. NF-kb is essential for Ifnb1 transcription in ECTV-infected monocytes. Deletion of the NF-kb-binding site from the Ifnb1 promoter (PRDII-/-) caused susceptibility to ECTV and WNV infections. IRF7 is critical to control both infections. PRDII-/-xIrf7-/- mice were as susceptible to ECTV as Ifnar1-/- but as susceptible to WNV as Irf7-/- mice. We found a predominant role for Ifnb1 over individual Ifna genes that depends on NF-kb-Ifnb1 binding. Yet, Ifna expansion is decisive to control WNV, indicating that NF-kb-IFN-β and IRF7-IFN-α non-redundantly sustain IFN-I production. Thus, IFN-I regulation and Ifna expansion evolved to differentially respond to DNA and RNA viruses. Funding Sources R01AI175567, R01AI169460, R21AI156490, R21AI153920, R21AI173837, R01AI110457, AAI Careers in Immunology Fellowship, NIAID Diversity Supplement Funds. Topic Categories Viral Immunology (VIR)