In summary, these studies show that primary human pDCs are largely resistant to rotavirus replication, but that they remain responsive and functional following viral exposure, as indicated by cellular activation, maturation and production of multiple cytokines, including TNFa and large amounts of IFNa. The pDC response is demonstrated to require both the viral dsRNA genome and acidification of the pDC endosome, implying the likely initiation of the type I IFN response by TLR7 or TLR9. To our knowledge, these data are the first to show that inactivated rotavirus can efficiently induce a type I IFN response, which differs from what has been seen in fibroblasts and epithelial cells exposed to rotavirus [62] . The restricted ability of rotavirus to replicate in pDCs, combined with the ability of the pDC to effect a type I IFN response in the absence of viral replication, likely serves the purposes of enabling the host to mount an innate antiviral response despite the efficient degradation of the IRFs by rotavirus NSP1 in many host cells. Combined with the novel dispensability of trypsin cleavage of VP4 for the initiation of the pDC response, this creates a mechanism for the establishment of an antiviral state in the systemic extraintestinal environment and likely contributes to the substantial restriction of systemic replication compared to that observed in the intestine [38] . These experiments also provide the first indication that rotavirus infection is capable of locally suppressing IFNa production in primary human cells. Importantly, these findings demonstrate that rotavirus infection of primary human pDCs provides a valuable experimental system for the study of cellular processes, receptors and signaling pathways underlying pDC-mediated antiviral immunity while revealing a potentially novel dsRNA-mediated pathway of IFNa induction.