Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
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DOI：
10.1371/journal.ppat.1001088
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发表时间：
2010-09-02
期刊：
影响因子：
6.7
通讯作者：
Fowler VG Jr
中科院分区：
文献类型：
--
作者：
Ahn SH;Deshmukh H;Johnson N;Cowell LG;Rude TH;Scott WK;Nelson CL;Zaas AK;Marchuk DA;Keum S;Lamlertthon S;Sharma-Kuinkel BK;Sempowski GD;Fowler VG Jr
虽然最近有研究表明，与C57BL/6J相比，A/J小鼠对金黄色葡萄球菌败血症高度易感，但导致这种差异表型的特定基因尚不清楚。利用染色体置换菌株，我们发现8、11和18号染色体上的基因座影响A/J小鼠对金黄色葡萄球菌败血症的易感性。然后，我们使用两种候选基因选择策略来识别这三条染色体上与金黄色葡萄球菌易感性相关的基因，以及两种基因选择策略所识别的目标基因。首先，我们使用全基因组转录图谱鉴定了191个(56个在CHR。8,100英镑。11和35。18)在感染金黄色葡萄球菌的A/J和C57BL/6J之间差异表达的三条染色体上的基因。其次，我们确定了两个对CHR感染后存活有显著影响的数量性状基因座(QTL)。18只用N_2回交小鼠(F1[C18A]×C57BL/6J)。CHR上有10个基因。18个(March3、Cep120、Chmp1b、Dcp2、Dtwd2、Isoc1、Lman1、Spire1、Tnfaip8和Seh1l)被定位到两个显著的QTL区域，并通过表达阵列选择策略进行了鉴定。实时荧光定量聚合酶链式反应显示，这10个基因中的6个(Chmp1b、Dtwd2、Isoc1、Lman1、Tnfaip8和Seh1l)在感染金黄色葡萄球菌的A/J和C57BL/6J之间的表达水平有显著差异。对于这6个基因中的两个基因(Tnfaip8和Seh11)，siRNA介导的基因表达被金黄色葡萄球菌攻击的RAW264.7巨噬细胞中的基因表达下调导致了与阴性对照相比细胞因子反应(IL-1β和GM-CSF)的显著变化。这些细胞因子的变化与金黄色葡萄球菌攻击的CSS18小鼠(含有A/J染色体18，但其他为C57BL/6J)小鼠的巨噬细胞一致，而不是C57BL/6J小鼠。这些发现表明，Tnfaip8和Seh11这两个基因可能与A/J小鼠对金黄色葡萄球菌的易感性有关，是研究人类遗传易感性的有希望的候选基因。金黄色葡萄球菌对人类的感染范围很广，从无症状的鼻腔携带到压倒性的败血症和死亡。小鼠模型为研究金黄色葡萄球菌感染等复杂疾病提供了一个有吸引力的策略。与C57BL/6J小鼠相比，A/J小鼠对金黄色葡萄球菌感染的易感性较高。我们利用染色体替代株(CS)证明了A/J中8、11和18号染色体上的基因与金黄色葡萄球菌的易感性有关。从这三条染色体上的∼4200基因中，我们鉴定了A/J和C57BL/6J在金黄色葡萄球菌攻击时差异表达的191个基因。接下来，我们在18号染色体上发现了两个重要的QTL，它们与氮气回交小鼠对金黄色葡萄球菌感染的易感性有关。有10个基因(March3、Cep120、Chmp1b、Dcp2、Dtwd2、Isoc1、Lman1、Spire1、Tnfaip8和Seh11)定位到这两个显著QTL上，并在A/J和C57BL/6J之间有差异表达。每个QTL上的一个基因Tnfaip8和Seh11影响暴露于金黄色葡萄球菌的小鼠巨噬细胞中细胞因子的表达。这些细胞因子反应模式与金黄色葡萄球菌攻击的CSS18巨噬细胞一致，但与C57BL/6J不同。Tnfaip8和Seh11是影响A/J小鼠金黄色葡萄球菌易感性基因的有力候选者。
Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies. Staphylococcus aureus has a wide spectrum of human infection, ranging from asymptomatic nasal carriage to overwhelming sepsis and death. Mouse models offer an attractive strategy for investigating complex diseases such as S. aureus infections. A/J mice are highly susceptible to S. aureus infection compared with C57BL/6J mice. We showed that genes on chromosomes 8, 11, and 18 in A/J are responsible for susceptibility to S. aureus by using chromosome substitution strains (CSS). From the ∼4200 genes on these three chromosomes, we identified 191 which were differentially expressed between A/J and C57BL/6J when challenged with S. aureus. Next, we identified two significant QTLs on chromosome 18 that are associated with susceptibility to S. aureus infection in N2 backcross mice. Ten genes (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTLs and were differentially expressed between A/J and C57BL/6J. One gene on each QTL, Tnfaip8 and Seh1l, affected expression of cytokines in mouse macrophages exposed to S. aureus. These cytokine response patterns were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18, but not C57BL/6J. Tnfaip8 and Seh1l are strong candidates for genes influencing susceptibility to S. aureus of A/J mice.
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影响因子：
4.8
作者：
Krewson, TD;Supelak, PJ;Palmert, MR
通讯作者：
Palmert, MR
影响因子：
1.9
作者：
Bullock, AE;Slobe, BS;Collins, AC
通讯作者：
Collins, AC
DOI：
10.1073/pnas.0307124101
发表时间：
2004-01-06
影响因子：
11.1
作者：
Kang, YS;Kim, JY;Park, CG
通讯作者：
Park, CG
影响因子：
5.6
作者：
HAMILTON, JA;STANLEY, ER;SHADDUCK, RK
通讯作者：
SHADDUCK, RK
影响因子：
3.1
作者：
CERQUETTI, MC;SORDELLI, DO;HOOKE, AM
通讯作者：
HOOKE, AM