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Porcine reproductive and respiratory syndrome (PRRS) is one of the most economic important diseases affect porcine industry worldwide.Current vaccines provide limited protection.Sn and CD163 are two essential receptors responsible for PRRSV infection of PAMs.To investigate the feasibility of amiRNAs targeting porcine Sialoadhesin (Sn) and CD163 for PRRSV control.Recombinant adenoviruses expressing amiRNA targeting porcine Sn and CD163 were generated. To enhance the feasibility of delivering amiRNA to PAMs,exosomes purified from rAds transduced porcine PK-15 cells were obtained and tested for transferring and antiviral efficiency.The additive anti-viral effect was observed.It showed that exosomes-containing amiRNAs could be transferred between porcine cells and inhibited PRRSV replication.The combination of rAds and exosomes treatment showed much higher gene inhibition efficiency (~78.1%) than single treated group To investigate the antiviral activities,PAMs pretreatment with either amiRNA induced a significant inhibition of PRRSV replication.Co-treatment with two amiRNAs resulted in higher reduction of antiviral activities (by ~2.6) than single treatment (by~1.5).Further studies showed that the amiRNAs targeting Sn and CD163 could inhibit replication of different strains of PRRSVs in PAMs Our study is the first attempt to inhibit PRRSV replication in PAMs through rAd transduction expressing amiRNAs targeting porcine Sn and CD163,enhanced by amiRNAs containing exosomes.It indicated the amiRNA interfering and recombinant adenovirus strategy might be applied as a novel mean for PRRSV control.