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mBio™ :鞭毛糖基化使幽门螺杆菌带毒性

来源:《微生物学》 2010-12-14 14:39

幽门螺杆菌存在于胃部及十二指肠的各个区域内。它会引起胃黏膜轻微的慢性发炎,甚至导致胃及十二指肠溃疡及胃癌。根据澳大利亚科学家日前在《微生物学》杂志上发表的一篇新论文,依赖维生素B6的鞭毛糖基化是幽门螺杆菌充分运动和具有毒性所必需的。

在生物体外,延长幽门螺杆菌的培育导致了传染性的丧失,以及在小鼠中造成了细菌负荷的减少,并且在低传染性隔离中被显著下调的基因被发现使用了整体的基因表达谱。于是墨尔本市莫纳什大学的Alexandra Grubman与法国巴黎的同事一道聚焦了两种基因,pdxJ和pdxA,它们分别被视为PdxJ和PdxA的编码同系物,是与吡哆醛-5-磷酸(PLP)——维生素B6的活化态——的全程合成有关的两种大肠杆菌蛋白质。

研究人员发现,幽门螺杆菌pdxJ无法被分裂,这意味着它可能是必不可少的。同基因型的幽门螺杆菌pdxA在形成突变后表现出了比亲代菌株更慢的生长速度。这种生长缺陷能够被PLP的加入,或是被pdxA的一个完整副本的引入所恢复。更进一步的研究表明,幽门螺杆菌pdxJ和pdxA能够在大肠杆菌中交叉补足一种PLP缺陷,意味着它们编码的蛋白质与维生素B6的生物合成有关。此外,小鼠感染研究显示,幽门螺杆菌的集群现象在缺乏一种pdxA的功能拷贝的情况下会极大地减少。

那么,维生素B6在集群中的确切功能到底是什么?在幽门螺杆菌中,维生素B6是PseC——鞭毛糖基化所需的一种转氨酶——的一种辅因子。对软琼脂板上的细菌活性进行的分析,以及活体细胞成像试验表明,pdxA突变是非能动的,并且电子显微镜显示,它们缺乏鞭毛。对整个细胞溶解产物,以及野生型和pdxA突变幽门螺杆菌的剪切鞭毛样本进行的分析显示,pdxA突变能够产生鞭毛蛋白A,但它并不能被输送到细胞表面,且不能被糖基化。

这是与维生素B6生物合成有关的酶首次作为一种细菌毒性因子被确定下来,同时研究人员推断,对维生素B6合成路径的破坏将带来新的疗法。(生物谷Bioon.com)

生物谷推荐原文出处:

mBio™   doi:10.1128/mBio.00112-10.

Vitamin B6 Is Required for Full Motility and Virulence in Helicobacter pylori

Alexandra Grubman a*, Alexandra Phillips a , Marie Thibonnier b*, Maria Kaparakis-Liaskos a*, Chad Johnson c , Jean-Michel Thiberge d*, Fiona J. Radcliff e , Chantal Ecobichon d*, Agnès Labigne d , Hilde de Reuse b , George L. Mendz f , and Richard L. Ferrero a,d*

ABSTRACT

Despite recent advances in our understanding of how Helicobacter pylori causes disease, the factors that allow this pathogen to persist in the stomach have not yet been fully characterized. To identify new virulence factors in H. pylori, we generated low-infectivity variants of a mouse-colonizing H. pylori strain using the classical technique of in vitro attenuation. The resulting variants and their highly infectious progenitor bacteria were then analyzed by global gene expression profiling. The gene expression levels of five open reading frames (ORFs) were significantly reduced in low-infectivity variants, with the most significant changes observed for ORFs HP1583 and HP1582. These ORFs were annotated as encoding homologs of the Escherichia coli vitamin B6 biosynthesis enzymes PdxA and PdxJ. Functional complementation studies with E. coli confirmed H. pylori PdxA and PdxJ to be bona fide homologs of vitamin B6 biosynthesis enzymes. Importantly, H. pylori PdxA was required for optimal growth in vitro and was shown to be essential for chronic colonization in mice. In addition to having a well-known metabolic role, vitamin B6 is necessary for the synthesis of glycosylated flagella and for flagellum-based motility in H. pylori. Thus, for the first time, we identify vitamin B6 biosynthesis enzymes as novel virulence factors in bacteria. Interestingly, pdxA and pdxJ orthologs are present in a number of human pathogens, but not in mammalian cells. We therefore propose that PdxA/J enzymes may represent ideal candidates for therapeutic targets against bacterial pathogens.

IMPORTANCE Approximately half of the world’s population is infected with H. pylori, yet how H. pylori bacteria establish chronic infections in human hosts remains elusive. From gene array studies, we identified two genes as representing potentially novel colonization factors for H. pylori. These genes encoded enzymes involved in the synthesis of vitamin B6, an important molecule for many metabolic reactions in living organisms. Little is currently known regarding vitamin B6 biosynthesis in human pathogens. We showed that mutant H. pylori bacteria lacking an enzyme involved in de novo vitamin B6 biosynthesis, PdxA, were unable to synthesize motility appendages (flagella) and were unable to establish chronic colonization in mice. Thus, this work identifies vitamin B6 biosynthesis enzymes as novel virulence factors for bacterial pathogens. Interestingly, a number of human pathogens, but not their mammalian hosts, possess these genes, which suggests that Pdx enzymes may represent ideal candidates for new therapeutic targets.

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