Long-lived C-elegans daf-2 mutants are resistant to bacterial pathogens
Long-lived C-elegans daf-2 mutants are resistant to bacterial pathogens
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DOI：
10.1126/science.1080147
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发表时间：
2003-06-20
期刊：
影响因子：
56.9
通讯作者：
Ausubel, FM
中科院分区：
文献类型：
--
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
我们的实验室研究了秀丽隐杆线虫的衰老机制（1，2）和免疫功能（3）。在这里，我们表明，管理这两个过程的机制可能是相互关联的。人类革兰氏阴性细菌病原体铜绿假单胞菌和肠道沙门氏菌以及革兰氏阳性病原体粪肠球菌和金黄色葡萄球菌可以杀死C。通过感染样过程感染线虫，在哺乳动物中的毒力和线虫中的杀灭所需的细菌因子之间存在显著的重叠（4，5）。此外，p38 MAPK（mitogen-activated protein kinase，丝裂原活化蛋白激酶）信号级联是C. elegans先天免疫反应，因为它是在哺乳动物（3）。这些实验确立了C.线虫作为研究细菌致病性和宿主免疫的有用模型。在这里，我们表明，某些长寿的C。线虫突变体对细菌病原体的杀伤具有高度抗性。为了研究长寿和病原体抗性之间的一般关系，我们测试了C。daf-2和age-1突变体对E.粪链球菌S.金黄色葡萄球菌和铜绿假单胞菌。daf-2编码一种胰岛素样受体，其在由age-1编码的磷脂酰肌醇3-激酶（PI 3-激酶）的上游起作用，并且daf-2或age-1中的部分功能丧失突变导致长寿表型（1）。daf-2和age-1突变体均能抵抗大肠杆菌的杀灭。粪链球菌S.金黄色葡萄球菌和铜绿假单胞菌（图1A;表S1）。最引人注目的是，相对于野生型C，daf-2（e1370）突变体的存活率增加了5 - 6倍。当暴露于革兰氏阳性病原体E. faecalis和S.金黄色葡萄球菌（图1A;表S1）。C.通过β 2胰岛素信号通路延长寿命elegans通过叉头转录因子β 1 - 16的去阻遏而发生，该因子通常处于β 1 - 2的负调控下。因此，daf-16的强功能丧失等位基因（如mgDf47）抑制了daf-2突变体的长寿表型（2）。daf-16（mgDf47）也抑制daf-2（e1370）的病原体抗性表型（图1A;表S1）。有趣的是，在所测定的实验条件下，daf-16突变体表现出与野生型蠕虫相当程度的对病原体介导的杀伤的易感性（图1A;表S1）。在这些实验中，daf-2（e1370）等位基因比daf-2（1368）等位基因和age-1（hx546）等位基因对细菌病原体更具抗性（图1A;表S1）。这很可能是daf-2和age-1突变体的等位基因强度差异的结果，所有这些突变体都是部分功能丧失突变体。
Our laboratories have studied the mechanisms of aging (1, 2) and immune function (3) in Caenorhabditis elegans. Herein we show that the mechanisms that govern these two processes may be interrelated. The human Gram-negative bacterial pathogens Pseudomonas aeruginosa and Salmonella enterica and the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus kill C. elegans by an infection-like process with remarkable overlap between the bacterial factors required for virulence in mammals and killing in nematodes (4, 5). Additionally, a p38 MAPK (mitogen-activated protein kinase) signaling cascade is a key component of the C. elegans innate immune response, as it is in mammals (3). These experiments establish C. elegans as a useful model for studying bacterial pathogenicity and host immunity. Here we show that certain long-lived C. elegans mutants are highly resistant to killing by bacterial pathogens. To investigate the general relation between longevity and pathogen resistance, we tested whether C. elegans daf-2 and age-1 mutants exhibit enhanced resistance to E. faecalis, S. aureus, and P. aeruginosa. daf-2 encodes an insulin-like receptor that functions upstream of the phosphatidylinositol 3-kinase (PI 3–kinase) encoded by age-1, and partial loss of function mutations in daf-2 or age-1 result in a long-lived phenotype (1). Both daf-2 and age-1 mutants were resistant to killing by E. faecalis, S. aureus, and P. aeruginosa (Fig. 1A; table S1). Most dramatic was the five-and sixfold increased survival of the daf-2 (e1370) mutants relative to wild-type C. elegans when exposed to the Gram-positive pathogens E. faecalis and S. aureus, respectively (Fig. 1A; table S1). Life-span extension through the DAF-2 insulin-signaling pathway in C. elegans occurs by de-repression of the forkhead transcription factor DAF-16, which is normally under negative regulation by DAF-2. Therefore, strong loss-of-function alleles of daf-16 such as mgDf47 suppress the long-lived phenotype of daf-2 mutants (2). daf-16 (mgDf47) also suppressed the pathogen-resistant phenotype of daf-2 (e1370)(Fig. 1A; table S1). Interestingly, the daf-16 mutant exhibited a comparable degree of susceptibility to pathogenmediated killing as wild-type worms (Fig. 1A; table S1) under the experimental conditions assayed. In these experiments, the daf-2 (e1370) allele was more resistant to bacterial pathogens than the daf-2 (1368) allele and the age-1 (hx546) allele (Fig. 1A; table S1). This is most likely a consequence of differences in allele strengths of the daf-2 and age-1 mutants, all of which are partial loss-of-function mutants.