Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.
Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.
复制标题
DOI：
10.1371/journal.pgen.0030152
复制
发表时间：
2007-09
期刊：
影响因子：
4.5
通讯作者：
Boyartchuk V
中科院分区：
文献类型：
--
作者：
Garifulin O;Qi Z;Shen H;Patnala S;Green MR;Boyartchuk V
宿主的遗传组成在感染的过程和结果中起着重要作用。近交系小鼠对单核细胞增生李斯特菌感染表现出广泛的敏感性，因此可以作为分析遗传多态性影响的良好模型。L.小鼠中的单核细胞增多症感染受到该细菌诱导干扰素β mRNA表达的能力的影响，所述干扰素β mRNA在小鼠中由Ifnb 1（干扰素β 1，成纤维细胞）基因编码。缺乏IFN β信号通路组分的小鼠品系对感染的抵抗力显著更强。我们发现，从ByJ亚株的常见的C57BL/6近交系小鼠的巨噬细胞在其诱导Ifnb1表达的能力受损，以响应细菌和病毒感染。我们将控制Ifnb1差异表达的基因定位到7号染色体上的一个区域，该区域包括干扰素调节因子3（Irf3），该因子编码一种负责早期诱导Ifnb1表达的转录因子。在C57 BL/6ByJ小鼠中，Irf3 mRNA的剪接效率低下，有很大比例的转录本保留内含子5。Irf3位点的分析确定了一个单碱基对多态性，并揭示了Irf3的内含子5是由非典型U12型剪接体剪接的。我们发现多态性破坏了U12型分支点，并对Irf3的剪接效率产生了深远的影响。我们证明了剪接控制元件中自然发生的变化对抗L有显著影响。单核细胞增多症因此，C57BL/6ByJ小鼠品系作为哺乳动物宿主如何通过引入非编码序列的细微改变来对抗细菌毒力策略的实例。个体DNA中的特定变异，称为遗传多态性，在确定感染性疾病的易感性方面可以发挥重要作用。鉴定与人类常见致病菌L.为了研究单核细胞增多症，我们使用对李斯特菌感染有差异易感性的密切相关的小鼠品系进行了一系列遗传和分子生物学实验。通过这种分析，我们已经确定了一个自发突变的内含子的Irf3基因，编码一个关键的转录因子参与先天免疫。这种单核苷酸变化影响Irf3 mRNA剪接的效率，从而限制了细菌诱导干扰素β表达以抑制先天免疫防御的能力。通过分析这种突变，我们发现小鼠Irf3 mRNA的加工依赖于非典型的U12剪接机制，该机制被认为是基因表达的限速步骤。我们的研究结果不仅提供了一个额外的例子，非编码多态性在基因功能的控制中的重要作用，而且还证明了这样的多态性可以微调先天免疫反应。
Genetic makeup of the host plays a significant role in the course and outcome of infection. Inbred strains of mice display a wide range of sensitivities to Listeria monocytogenes infection and thus serve as a good model for analysis of the effect of genetic polymorphism. The outcome of L. monocytogenes infection in mice is influenced by the ability of this bacterium to induce expression of interferon beta mRNA, encoded in mouse by the Ifnb1 (interferon beta 1, fibroblast) gene. Mouse strains that lack components of the IFNβ signaling pathway are substantially more resistant to infection. We found that macrophages from the ByJ substrain of the common C57BL/6 inbred strain of mice are impaired in their ability to induce Ifnb1 expression in response to bacterial and viral infections. We mapped the locus that controls differential expression of Ifnb1 to a region on Chromosome 7 that includes interferon regulatory factor 3 (Irf3), which encodes a transcription factor responsible for early induction of Ifnb1 expression. In C57BL/6ByJ mice, Irf3 mRNA was inefficiently spliced, with a significant proportion of the transcripts retaining intron 5. Analysis of the Irf3 locus identified a single base-pair polymorphism and revealed that intron 5 of Irf3 is spliced by the atypical U12-type spliceosome. We found that the polymorphism disrupts a U12-type branchpoint and has a profound effect on the efficiency of splicing of Irf3. We demonstrate that a naturally occurring change in the splicing control element has a dramatic effect on the resistance to L. monocytogenes infection. Thus, the C57BL/6ByJ mouse strain serves as an example of how a mammalian host can counter bacterial virulence strategies by introducing subtle alteration of noncoding sequences. Specific variances in an individual's DNA, known as genetic polymorphisms, can play a significant role in determining susceptibility to an infectious disease. To identify the genetic polymorphisms that are associated with resistance to the common human bacterial pathogen L. monocytogenes, we have carried out a series of genetic and molecular biology experiments using closely related strains of mice that are differentially susceptible to Listeria infection. Through this analysis, we have identified a spontaneous mutation in an intron of the Irf3 gene, which encodes a key transcription factor involved in innate immunity. This single nucleotide change affects the efficiency with which Irf3 mRNA is spliced, thus limiting the ability of bacteria to induce interferon beta expression in order to suppress innate immune defense. By analyzing this mutation, we found that processing of mouse Irf3 mRNA relies on an atypical U12 splicing mechanism that has been suggested to be a rate-limiting step in gene expression. Our findings not only provide an additional example of an important role of noncoding polymorphisms in control of gene function, but also demonstrate how such polymorphisms can fine tune innate immune response.
登录
查看更多内容
影响因子：
1.5
作者：
OGAWA, Y;OHNO, N;SUDO, T
通讯作者：
SUDO, T
影响因子：
5.3
作者：
Karpova, AY;Ronco, LV;Howley, PM
通讯作者：
Howley, PM
影响因子：
30.8
作者：
DIETRICH, WF;MILLER, JC;LANDER, ES
通讯作者：
LANDER, ES
影响因子：
5.4
作者：
Hwang, DY;Cohen, JB
通讯作者：
Cohen, JB
影响因子：
2.2
作者：
KREUZBURGDUFFY, UCK;MACDONALD, C
通讯作者：
MACDONALD, C