Susceptibility to anthrax lethal toxin is controlled by three linked quantitative trait loci
Susceptibility to anthrax lethal toxin is controlled by three linked quantitative trait loci
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DOI：
10.1016/s0002-9440(10)63532-8
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发表时间：
2003-11-01
影响因子：
6
通讯作者：
Teuscher, C
中科院分区：
文献类型：
--
作者：
McAllister, RD;Singh, Y;Teuscher, C
炭疽致死毒素(LT)是炭疽杆菌感染后致死病理的主要致病因子。巨噬细胞是介导致死性的主要效应细胞，因为巨噬细胞耗竭的小鼠对LT攻击具有抵抗力。最近，控制小鼠巨噬细胞体外暴露于LT后对细胞溶解的差异敏感性的基因Ltxs1被鉴定为Kif1c。为了在体内直接评估Kif1c等位基因在死亡率中的作用，我们在LT敏感的BALB/c背景下，研究了一组携带来自LT抗性DBA/2小鼠的中央11号染色体不同片段的区间特异性重组同源基因系。本研究的结果表明，致死率受3个连锁数量性状基因座(QTL)控制，它们分别是Litxs1/Kif1c(42-43 cM)、Litxs2(35-37 cM)和Litxs3(45-47 cM)。该区间包含NOS2，NOS2是一个很有吸引力的候选基因。在这一点上，我们证明了在体内选择性地、基于药物的抑制NOS2活性可以部分地推翻对LT的遗传耐药性，并且通过逆转录-聚合酶链式反应检测到的NOS2在DBA/2和BALB/c巨噬细胞中的表达存在显著差异。此外，为了概括(BALB/c×DBA/2)F，杂种，所有三个QTL上都需要DBA/2等位基因。
Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with Bacillus anthracis. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently, Ltxs1, the gene controlling differential susceptibility of murine macrophages to cytolysis following In vitro exposure to LT, was identified as Kif1c. To directly assess the in vivo role of Kif1c alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL): Ltxs1/Kif1c (42-43 cM), Ltxs2 (35-37 cM), and Ltxs3 (45-47 cM). The Ltxs3 interval encompasses Nos2, which is an attractive candidate gene for Ltxs3. in this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity in vivo partially overrides genetic resistance to LT and that Nos2 expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c X DBA/2) F, hybrids, DBA/2 alleles are required at all three QTL.