Peripheral pDCs likely represent a significant source of the systemic IFNa observed following in vivo rotavirus infection [43, 72, 73, 74] ; the dispensability of proteolytic activation of VP4 for pDC infection and IFNa stimulation by rotavirus provides a mechanism for the establishment of the antiviral state extraintestinally by a small amount of virus. Increased levels of serum IFNa have been reported in human pediatric patients infected with rotavirus [43, 44] ; levels peaked within two days of symptom onset and disease resolved more quickly in patients with the highest levels of IFNa [43] . Likewise, type I IFN responses were observed in newborn calves infected with bovine rotavirus: animals receiving both high and low doses of viral inoculums generated multiple waves of IFN production, with higher doses correlating with both more rapid IFN responses and a lack of clinical signs [74] . As the ability of type I IFN to activate multiple arms of the innate and adaptive immune response is well documented (reviewed in [75, 76, 77] ), and recent data have shown that type I IFN plays a critical role in restricting systemic rotavirus infection [78] , we predict that pDC-derived type I IFN plays a significant role in confining rotavirus replication to the intestine while initiating the systemic immune response in the periphery.