As a consequence of their effects on ectodomain shedding,members of the Adisintegrin and metalloprotease(ADAM)family have been implicated in the control of various cellular processes.Although ADAM family members are also involved in cancer,inflammation,and other pathologies,it's unclear whether theyaffectporcine reproductive and respiratory syndrome virus(PRRSV)infection.Here,we demonstrate for the first time that inhibition of ADAM17 enhances PRRSV attachment/entryin Marc-145 and porcine alveolar macrophages(PAMs).We also demonstratethatinhibition of ADAM17 up-regulates membrane CD163 expression,a putative PRRSV receptor that isexogenously expressed in BHK-21 and endogenously expressed in Marc-145 and PAMs.Furthermore,overexpression of ADAM17 induced down-regulation of CD163 expression and a reduction in PRRSV infection,whereas ablation of ADAM17 expression using specific siRNAresulted in up-regulation of CD163 expression with a correspondingincrease in PRRSV infection.These ADAM17-mediated effects were confirmed with PRRSV non-permissive BHK-21 cells transfected with CD163 cDNA.Overall,these findings indicate that ADAM17 down-regulates CD163 expression and hinders PRRSV infection.