Induction of type I IFNs was shown to be critical for some innate immune responses to Ads [10] .We therefore investigated whether a characteristic consequence of infection with Ad, the induction of LPS hypersensitivity [72] , might be mediated by type I IFNs. For this purpose, we infected wt and IFNabR 2/2 mice with Ads, challenged them 16 h later with LPS and measured the TNF-a response. Non-infected LPS-treated mice served as a control. Unlike the infected wt mice, the Ad3-infected IFNabR 2/2 mice did not exhibit enhanced responses to LPS (Fig. 11A) . Interestingly, LPS hypersensitivity developed also in mice injected with very small amounts of Ad. Such amounts were capable of the elicitation of IFN-b mRNA in the spleen of infected animals, but incapable of inducing detectable circulating IFN-ab ( Fig. S14A and  B) . Similar results were obtained in Ad5-GFP-infected mice (not shown). Furthermore, in IRF-7 2/2 mice that exhibit a severe impairment of the IFN-ab response to Ad a severe impairment of LPS sensitization by Ad5-GFP was also observed. (Fig. 11B) . In contrast, sensitization to LPS developed normally in Ad5-GFPinfected TLR9 2/2 mice (Fig. 11B) , which is in agreement with our finding that TLR9 is not critical for the induction of IFN-ab by Ad. Furthermore, only Ad5-GFP-infected wt, but not IFNabR 2/2 mice exhibited enhanced susceptibility to LPS shock (Fig. 11C) . Notably, also Ad vector-infected or IFN-a treated human monocyte-derived mDCs exhibited enhanced sensitivity to LPS and overproduced TNF-a upon LPS challenge (Fig. S14C) . On the whole, our results indicate that IFN-ab is an essential mediator of the LPS hypersensitivity induced by adenovirus infection.