Peli1 negatively regulates type I interferon induction and antiviral immunity in the CNS

BACKGROUND: Type I interferons (IFN-Is) serve as mediators of antiviral innate immunity and also regulate adaptive immune responses. The molecular mechanism that regulates virus-induced IFN-I production, particularly in tissue-resident immune cells, is incompletely understood. RESULTS: Here we identified the E3 ubiquitin ligase Peli1 as a negative regulator of IFN-I induction in microglia, innate immune cells of the central nervous system (CNS). Peli1 deficiency profoundly promoted IFN-β expression in microglia in response to in vitro stimulation by toll-like receptor (TLR) ligands or a CNS-tropic virus, the vascular stomatitis virus (VSV). Upon intranasal infection with VSV, the Peli1-deficient mice displayed heightened in vivo IFN-I responses in the CNS, coupled with reduced brain viral titer and increased survival rate. CONCLUSIONS: These results establish Peli1 as an innate immune regulator in the CNS that modulates the threshold of IFN-I responses against viral infections.