Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin (Nat Genet, doi:10.1038/ng1724)

報告日期: 2006/05/16
報告時間: 15:10/16:00
報告學生: 莊懷佳
講評老師: 鄧景浩
附件下載:
http://basicmed.med.ncku.edu.tw/upload_data/950516-1.pdf

 

Nalp1b Controls Mouse Macrophage Susceptibility to Anthrax Lethal Toxin

Eric D Boyden & William F Dietrich

Nature Genetics 38, 240 - 244 (2006)

講評老師:鄧景浩 老師                 時間:2006.5.16 PM 3:00

演講者:莊懷佳                        地點:Room 602

 

Anthrax, an infectious disease caused by Bacillus anthracis, is caused by the production of anthrax toxins. Among these toxin factors, lethal factor (LF) is responsible for fatal systemic infections with rapid necrosis of macrophage. Therefore, the mechanism of LF-induced macrophage cytolysis should be clarified. Since LF is a zinc metallopeptidase, LF may cleave an unknown target protein, which subsequently leads to cytolysis. In previous studies, the authors have shown that the locus Ltxs1, mapping to the chromosome 11, may contribute to sensibility of LeTx (lethal toxin, containing LF and protective antigen) by contrasting the inbred mouse stains1. They have identified a candidate gene, Kif1c, as a substrate of LF. However, as a potential susceptible gene, Kif1c was still presented on LeTx-resistant macrophages of the two inbred mouse stains. In order to rebuild their study, the sequence of the genomic interval was improved for better assays. In this study, a new candidate gene on locus Ltxs1, Nalp1b, was found. Nalp1b, belonges to a superfamily of intracellular proteins that regulate innate immunity or inflammation, and possesses an extremely polymorphic gene in different mouse stains. The authors then created transgenic mice with the susceptible allele of Nalp1b on the resistant strains, whose macrophages showed susceptibility to LeTx. Conversely, inhibition of Nalp1b expression resulted in resistibility of susceptible macrophage to LeTx. Moreover, the authors also indicated that the activation of caspase-1 was required for LeTx-induced macrophage death. Collectively, this study provided the evidence that Nalp1b may be as a key determinant for LeTx susceptibility, which also conferred the basis of development of anthrax treatment 2.

Reference:

        1.  Roberts JE, Watters JW, Ballard JD, Dietrich WF. Ltx1, a mouse locus that influences the susceptibility of macrophages to cytolysis caused by intoxication with Bacillus anthracis lethal factor, maps to chromosome 11. Mol Microbiol. 1998;29:581-591

        2.  Bugge TH, Leppla SH. Anthrax target in macrophages unveiled. Nat Genet. 2006;38:137-138