Found at: doi:10.1371/journal.ppat.1000196.s002 (4.87 MB TIF) Biodefense versus bioterrorism Genomics was essential for identifying the source of the deadly anthrax strain released after the September 11 terrorist attacks in the US. The same research that is needed to combat low-probability bioterror attacks is needed to combat high-probability natural infectious agents.  Key Role of Splenic Myeloid DCs in the IFN-αβ Response to Adenoviruses In Vivo The early systemic production of interferon (IFN)-αβ is an essential component of the antiviral host defense mechanisms, but is also thought to contribute to the toxic side effects accompanying gene therapy with adenoviral vectors. Here we investigated the IFN-αβ response to human adenoviruses (Ads) in mice. By comparing the responses of normal, myeloid (m)DC- and plasmacytoid (p)DC-depleted mice and by measuring IFN-αβ mRNA expression in different organs and cells types, we show that in vivo, Ads elicit strong and rapid IFN-αβ production, almost exclusively in splenic mDCs. Using knockout mice, various strains of Ads (wild type, mutant and UV-inactivated) and MAP kinase inhibitors, we demonstrate that the Ad-induced IFN-αβ response does not require Toll-like receptors (TLR), known cytosolic sensors of RNA (RIG-I/MDA-5) and DNA (DAI) recognition and interferon regulatory factor (IRF)-3, but is dependent on viral endosomal escape, signaling via the MAP kinase SAPK/JNK and IRF-7. Furthermore, we show that Ads induce IFN-αβ and IL-6 in vivo by distinct pathways and confirm that IFN-αβ positively regulates the IL-6 response. Finally, by measuring TNF-α responses to LPS in Ad-infected wild type and IFN-αβR(−/−) mice, we show that IFN-αβ is the key mediator of Ad-induced hypersensitivity to LPS. These findings indicate that, like endosomal TLR signaling in pDCs, TLR-independent virus recognition in splenic mDCs can also produce a robust early IFN-αβ response, which is responsible for the bulk of IFN-αβ production induced by adenovirus in vivo. The signaling requirements are different from known TLR-dependent or cytosolic IFN-αβ induction mechanisms and suggest a novel cytosolic viral induction pathway. The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease. Adenoviruses (Ads) cause mild disease in humans, but are hazardous pathogens in immuno-compromised individuals [1] . Human Ads are dsDNA viruses grouped into six species. Species A, C, D, E, and F and species B Ads use different infectious entry pathways [2] . Human Ads enter mouse cells and express their early genes; however, the virus genome is not replicated and no viral progeny is made during the infection of mouse cells in vitro or in vivo [3, 4] . Furthermore, early viral gene expression can be abolished by UV-inactivation and well-defined mutants with defects of viral early genes or viral entry are available [3, 5] . Thus, the effects elicited by different components of the virus-host interaction preceding viral replication can be accurately evaluated.