Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1β accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1β expression in response to BA spores is required for anti-BA host defenses. Caspase-1–/– and IL-1β–/– mice are more susceptible than wild-type (WT) mice to lethal BA infection, are less able to kill BA both in vivo and in vitro, and addition of rIL-1β to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1β and nitric oxide, by which BA are killed in WT but not in caspase-1–/– mice, suggesting that the spore itself stimulated inflammatory responses. While spores induced IL-1β in LT-susceptible and -resistant macrophages, LT induced IL-1β only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1β. While both spores and LT induced caspase-1 activity and IL-1β, LT did not induce IL-1β mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1β by distinct signaling pathways. Whereas the spore-induced IL-1β limits BA infection, LT-induced IL-1β enables BA to escape host defenses. Supporting Information for this article is available at www.wiley-vch.de/contents/jc_2040/2008/38141_s.pdf