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Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

Abstract

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 infections1. EF and LF can be transported by PA into the cytosol of many cell types2. In mouse macrophages, LF can cause rapid necrosis that may be related to the pathology of systemic infections3,4,5. Inbred mouse strains display variable sensitivity to LeTx-induced macrophage necrosis6,7. 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.

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Figure 1: NOD and SJL macrophages are resistant to LeTx despite carrying the Leu578 Kif1c allele, and the trait maps to Ltxs1.
Figure 2: Nalp1b has at least five heavily polymorphic alleles and is the only paralogue expressed in 129S1 macrophages.
Figure 3: A Nalp1b transgene derived from 129S1 renders resistant macrophages fully susceptible to LeTx.
Figure 4: Inhibition of Nalp1b expression renders susceptible macrophages partially resistant to LeTx.
Figure 5: Caspase-1 is activated in susceptible macrophages upon treatment with LeTx and is required for susceptibility.

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Acknowledgements

We thank A. Abney, S. Goodart, E. Kazyanskaya, K. McAuliffe and K. Sadigh for technical assistance; J. Watters and members of the Dietrich laboratory for helpful discussion and S. Boyden, L. Boyden, N. Andrews, F. Ausubel, L. Kunkel and R. Mosher for critical reading of the manuscript.

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Correspondence to William F Dietrich.

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Supplementary information

Supplementary Fig. 1

Translated sequence alignment of Nalp1b alleles 1–5. (PDF 74 kb)

Supplementary Table 1

Primer and morpholino sequences. (PDF 71 kb)

Supplementary Note (PDF 1855 kb)

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Boyden, E., Dietrich, W. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38, 240–244 (2006). https://doi.org/10.1038/ng1724

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