Peste des Petits Ruminants Virus-Induced Novel MicroRNA miR-3 Contributes To Inhibit Type I IFN Production by Targeting IRAK1

ABSTRACT

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 type I interferon (IFN-I) responses. We report that a novel microRNA in goat peripheral blood mononuclear cells (PBMCs) called miR-3 is 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 pathways may be involved in the induction of miR-3 during PPRV infection. Importantly, we demonstrated that miR-3 was a potent negative regulator of IFN-α production by targeting interleukin-1 receptor-associated kinase 1 (IRAK1), which resulted in the enhancement of PPRV infection. In addition, we found that PPRV infection can activate interferon-stimulated genes (ISGs) through IFN-independent and IRF3-dependent pathways. Moreover, our data revealed that miR-3-mediated regulation of IFN-α production may be involved in the differential susceptibility between goat and sheep to PPRV. Taken together, our findings identify a new strategy by PPRV to escape IFN-I-mediated antiviral immune responses by engaging cellular microRNA, and thus leads to improved understanding of PPRV pathogenesis.

IMPORTANCE Peste des petits ruminants virus (PPRV) induces in the host a transient but severe immunosuppression, which threatens both small livestock and endangered susceptible wildlife populations in many countries. Despite extensive research, the mechanism underlying PPRV immune system evasion remains elusive. Our data provide the first direct evidence that a novel microRNA-3 (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 miR-3 was identified as IRAK1, which is important for type I IFN production. Moreover, we identified NF-κB and p38 pathways as possibly involved in 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.