Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

• Published in: Nature genetics Vol. 38; no. 2; pp. 240 - 244
• Main Authors: Dietrich, William F, Boyden, Eric D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2006; Nature Publishing Group
• Subjects: Agriculture; Alleles; Animal Genetics and Genomics; Animals; Anthrax; Antigens, Bacterial - toxicity; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - metabolism; Bacillus anthracis; Bacterial toxins; Bacterial Toxins - toxicity; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspase 1 - metabolism; Cell Survival; Cellular biology; Complications and side effects; Diagnosis; Disease Susceptibility; Edema; Enzymes; Exons - genetics; Fundamental and applied biological sciences. Psychology; Gene Function; Gene loci; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Human Genetics; letter; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Transgenic; Molecular Sequence Data; Mortality; Pathology; Physiological aspects; Polymorphism, Genetic; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Toxins; United States; Infection; Toxin; Vertebrata; Regulation(control); Mammalia; Mouse; Anthrax; Rodentia; Bacteriosis; Macrophage
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1724

The pathogenesis of Bacillus anthracis, the bacterium that causes anthrax, depends on secretion of three factors that combine to form two bipartite toxins. Edema toxin, consisting of protective antigen (PA) and edema factor (EF), causes the edema associated with cutaneous anthrax infections, whereas lethal toxin (LeTx), consisting of PA and lethal factor (LF), is believed to be responsible for causing death in systemic anthrax infections. EF and LF can be transported by PA into the cytosol of many cell types. In mouse macrophages, LF can cause rapid necrosis that may be related to the pathology of systemic infections. Inbred mouse strains display variable sensitivity to LeTx-induced macrophage necrosis. This trait difference has been mapped to a locus on chromosome 11 named Ltxs1 (refs. 7,8). Here we show that an extremely polymorphic gene in this locus, Nalp1b, is the primary mediator of mouse macrophage susceptibility to LeTx. We also show that LeTx-induced macrophage death requires caspase-1, which is activated in susceptible, but not resistant, macrophages after intoxication, suggesting that Nalp1b directly or indirectly activates caspase-1 in response to LeTx.