Bacillus anthracis spores and lethal toxin induce IL-1beta via functionally distinct signaling pathways.
Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1beta accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1beta expression in response to BA spores is required for anti-BA host defenses. Caspase-1(-/-) and IL-1beta(-/-) 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-1beta to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1beta 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-1beta in LT-susceptible and -resistant macrophages, LT induced IL-1beta only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1beta. While both spores and LT induced caspase-1 activity and IL-1beta, LT did not induce IL-1beta mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1beta by distinct signaling pathways. Whereas the spore-induced IL-1beta limits BA infection, LT-induced IL-1beta enables BA to escape host defenses.
Kang
Tae Jin
TJ
Center for Vaccine Development, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Basu
Subhendu
S
Zhang
Lei
L
Thomas
Karen E
KE
Vogel
Stefanie N
SN
Baillie
Les
L
Cross
Alan S
AS
D000825:Animal Structures / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D000881:Anthrax / Q000276:immunology; D000942:Antigens, Bacterial / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001408:Bacillus anthracis / Q000276:immunology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013171:Spores, Bacterial / Q000276:immunology*; D019311:Staurosporine / Q000494:pharmacology; D016019:Survival Analysis
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C030325:anthrax toxin; D015638:Cytochalasin D; D009569:Nitric Oxide; D003513:Cycloheximide; D020170:Caspase 1; D019311:Staurosporine