Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1.
Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1.
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DOI：
10.1371/journal.ppat.1000906
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发表时间：
2010-05-20
期刊：
影响因子：
6.7
通讯作者：
Moayeri M
中科院分区：
文献类型：
--
作者：
Newman ZL;Printz MP;Liu S;Crown D;Breen L;Miller-Randolph S;Flodman P;Leppla SH;Moayeri M
炭疽致死毒素（Anthrax lethal toxin，LT）是一种含有蛋白酶的双组分毒素，是炭疽杆菌的关键毒力决定因子。在小鼠中，LT导致从某些近交系分离的巨噬细胞的快速溶解，但小鼠巨噬细胞敏感性和小鼠品系对毒素攻击的敏感性之间的相关性较差。在大鼠中，LT通过未知的机制在短短37分钟内诱导快速死亡。我们使用了一个重组近交系（RI）大鼠面板的19株LT敏感和LT耐药的祖细胞映射LT的敏感性在大鼠染色体10上的一个位点，其中包括炎性小体NOD样受体（NLR）传感器，Nlrp 1。该基因是最接近的大鼠同源小鼠Nlrp 1b，这是以前被证明控制小鼠巨噬细胞对LT的敏感性。在体外巨噬细胞对LT诱导的裂解和动物对毒素的敏感性之间的绝对相关性被发现为19 RI株和12个额外的大鼠品系。从这些菌株的Nlrp 1测序确定了5个多态性等位基因。Nlrp 1蛋白N-末端100个氨基酸内的多态性与LT敏感性完全相关。这些数据表明，大鼠中毒素介导的致死性以及该动物模型中的巨噬细胞敏感性由10号染色体上的单个位点控制，该位点可能是炎性体NLR传感器Nlrp 1。炎性小体是多蛋白质胞质复合物，其通过激活宿主先天免疫应答来响应各种危险信号。这些复合物的传感器组分是NLR（NOD样受体）蛋白。在这份报告中，一个重组近交系大鼠品系收集用于遗传地图炭疽致死毒素（LT）的易感性，染色体10的有限区域含有一个这样的传感器，Nlrp 1。类似于其小鼠直系同源物，Nlrp 1b，控制小鼠巨噬细胞对这种毒素的敏感性，含有大鼠Nlrp 1的基因座被证明控制巨噬细胞对炭疽LT的敏感性。然而，与小鼠中多个遗传基因座影响动物对LT的敏感性的情况不同，单个染色体10基因座似乎单独控制炭疽LT诱导的快速死亡，这种死亡可能发生在短短37分钟内。从12个大鼠品系的Nlrp 1的测序确定的多态性与动物的毒素敏感性完全相关。这些多态性在Nlrp 1的N-末端100个氨基酸的部分内，在未知功能的区域中，这表明啮齿动物Nlrp 1的N-末端可能是一个重要的功能域。
Anthrax lethal toxin (LT) is a bipartite protease-containing toxin and a key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis of macrophages isolated from certain inbred strains, but the correlation between murine macrophage sensitivity and mouse strain susceptibility to toxin challenge is poor. In rats, LT induces a rapid death in as little as 37 minutes through unknown mechanisms. We used a recombinant inbred (RI) rat panel of 19 strains generated from LT-sensitive and LT-resistant progenitors to map LT sensitivity in rats to a locus on chromosome 10 that includes the inflammasome NOD-like receptor (NLR) sensor, Nlrp1. This gene is the closest rat homolog of mouse Nlrp1b, which was previously shown to control murine macrophage sensitivity to LT. An absolute correlation between in vitro macrophage sensitivity to LT-induced lysis and animal susceptibility to the toxin was found for the 19 RI strains and 12 additional rat strains. Sequencing Nlrp1 from these strains identified five polymorphic alleles. Polymorphisms within the N-terminal 100 amino acids of the Nlrp1 protein were perfectly correlated with LT sensitivity. These data suggest that toxin-mediated lethality in rats as well as macrophage sensitivity in this animal model are controlled by a single locus on chromosome 10 that is likely to be the inflammasome NLR sensor, Nlrp1. Inflammasomes are multiprotein cytoplasmic complexes that respond to a variety of danger signals by activating the host innate immune response. The sensor components of these complexes are NLR (NOD-like receptor) proteins. In this report, a recombinant inbred rat strain collection was used to genetically map anthrax lethal toxin (LT) susceptibility to a limited region of chromosome 10 containing one such sensor, Nlrp1. Similar to its mouse ortholog, Nlrp1b, which controls murine macrophage sensitivity to this toxin, the locus containing rat Nlrp1 was shown to control macrophage sensitivity to anthrax LT. However, unlike the situation in mice, where multiple genetic loci influence animal susceptibility to LT, the single chromosome 10 locus alone appears to control the rapid anthrax LT-induced death, which can occur in as little as 37 minutes. Sequencing of Nlrp1 from 12 rat strains identified polymorphisms which correlated perfectly with animal sensitivity to toxin. These polymorphisms were within the N-terminal 100-amino acid portion of Nlrp1, in an area of unknown function, which suggests that the N-terminus of rodent Nlrp1 could be an important functional domain.
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影响因子：
3.2
作者：
BEALL, FA;TAYLOR, MJ;THORNE, CB
通讯作者：
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影响因子：
16
作者：
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作者：
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DOI：
10.1152/ajpregu.00593.2003
发表时间：
2004-04-01
影响因子：
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作者：
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通讯作者：
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影响因子：
9.2
作者：
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通讯作者：
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