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.

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.

These results establish Peli1 as an innate immune regulator in the CNS that modulates the threshold of IFN-I responses against viral infections.