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Peste des petits ruminants virus (PPRV) is an important pathogen that seriously influences the productivity of small ruminants worldwide. PPRV has evolved several mechanisms to evade IFN-I responses. We report that a novel microRNA in goat PBMCs, novel miR-3, was upregulated by PPRV to facilitate virus infection. Furthermore, PPRV V protein alone was sufficient to induce novel miR-3 expression, and NF-κB and p38 pathway may involved in the induction of novel miR-3 during PPRV infection. Importantly, we demonstrated that novel miR-3 was a potent negative regulator of IFN-α production by targeting IRAK1, which resulted in the enhancement of PPRV infection. In addition, we found that PPRV infection can activated ISGs through IFN independent and IRF3 dependent pathway. Moreover, our data revealed that novel miR-3 mediated regulation of IFN-α production may involve in the differential susceptibility between goat and sheep to PPRV. Taken together, our findings identified a new strategy taken by PPRV to escape IFN-I-mediated antiviral immune responses by engaging cellular microRNA and, thus, improve our understanding of its pathogenesis. IMPORTANCE: Peste des petits ruminants virus (PPRV) induce in the hosts a transient but severe immunosuppression, which threatens both small livestock and endangered susceptible wildlife populations in many countries. Despite extensive research has been explored, the mechanism underlying PPRV immune system evasion remains elusive. Our data provided the first direct evidence that novel microRNA-3 (novel miR-3) feedback inhibits type I IFN signaling when goat PBMCs are infected with PPRV vaccine strain N75/1, thus promoting the infection. In this study, the target of novel miR-3, IRAK1, which are important for PPRV-induced type I IFN production, have also been found. Moreover, we identified NF-κB and p38 pathways may involve in novel miR-3 induction in response to PPRV infection. Taken together, our research has provided new insight into understanding the effects of miRNA on host-virus interactions, and revealed a potential therapeutic target for antiviral intervention., (Copyright © 2021 American Society for Microbiology.)