| Anthrax is a potentially fatal infectious disease caused by Bacillus anthracis. Its pathogenicity depends on the secretion of two toxins that attack the innate immune system, edema toxin and lethal toxin. Lethal toxin induces rapid necrotic cytolysis of macrophages from many inbred mouse strains, but macrophages from some strains are immune to this effect, which implies that the trait is under the control of one or more genetic loci. Previously, the trait was mapped to a single locus on chromosome 11 named Ltxs1, and Kif1c, which encodes a kinesin involved in Golgi to ER trafficking, was proposed as a candidate gene.; We have identified two inbred mouse strains that have resistant macrophages but carry a "susceptible" Kif1c allele. Using congenic, recombinant congenic, and recombinant inbred mice, we mapped the trait in both strains to a region of chromosome 11 that overlaps the Ltxs1 locus. Since expression of Kif1c does not vary substantially between strains, we inferred that a different gene in or near the Ltxs1 locus influences macrophage susceptibility to lethal toxin. Nalp1, a previously uncharacterized member of a family of genes involved in inflammation and innate immunity, had originally been excluded as a candidate gene for Ltxs1 due to an inability to detect expression. We have now shown that one of three tandem Nalp1 paralogs, Nalp1b, is expressed and contains polymorphisms that are consistent with the macrophage phenotypes of all examined mouse strains. In addition, macrophages from transgenic mice that express a susceptible Nalp1b allele on a resistant genetic background are completely susceptible to lethal toxin, whereas inhibiting Nalp1b expression renders susceptible macrophages partially resistant to lethal toxin. These data conclusively demonstrate that Nalp1b is the Ltxs1 gene.; We have also shown that caspase-1, the main activator of the inflammatory cytokines interleukin-1beta and -18 and a target of human NALP1, is required for lethal toxin-stimulated mouse macrophage cytolysis since macrophages that carry a susceptible Nalp1b allele and a null allele of Casp1 are resistant to lethal toxin. Furthermore, caspase-1 is activated upon intoxication of susceptible macrophages, but not resistant macrophages, which indicates that Nalp1b is involved in caspase-1 activation. |
