The Mycobacterium tuberculosis PhoPR two‐component system regulates genes essential for virulence and complex lipid biosynthesis
The Mycobacterium tuberculosis PhoPR two‐component system regulates genes essential for virulence and complex lipid biosynthesis
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DOI：
10.1111/j.1365-2958.2006.05102.x
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发表时间：
2006-04
影响因子：
3.6
通讯作者：
Shaun B. Walters;E. Dubnau;I. Kolesnikova;F. Laval;M. Daffé;I. Smith
中科院分区：
文献类型：
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作者：
Shaun B. Walters;E. Dubnau;I. Kolesnikova;F. Laval;M. Daffé;I. Smith
双组分信号转导系统（2-CS）在细菌致病过程中起着重要作用。在这里介绍的工作中，我们研究了结核分枝杆菌（Mtb）PhoPR 2-CS突变对这种细菌病原体的致病性，生理学和全局基因表达的影响。PhoPR的破坏导致巨噬细胞和小鼠的生长显著减弱，并阻止在低Mg 2+培养基中的生长。THP-1巨噬细胞无法生长，可以通过在感染过程中加入过量的Mg 2+来部分克服。全局转录测定表明PhoP是几种基因的正转录调节因子，但不支持Mtb PhoPR系统感知Mg 2+饥饿的假设，如鼠伤寒沙门氏菌PhoPQ 2-CS的情况。被正向调节的基因包括在分别编码用于生物合成硫化物和二酰基海藻糖和多酰基海藻糖的酶的pks 2和msl 3基因簇中发现的那些基因。补充的生物化学研究，与另一组最近的结果一致，表明这些复合脂质也不存在于phoP突变体中，并且在其细胞包膜中缺乏这些组分可能间接导致突变体的高-Mg 2+生长需求。本文报道的实验提供了PhoPR 2-CS参与Mtb发病机制的功能证据，并且它们表明在phoP突变体中观察到的衰减的主要原因是缺乏已知对毒力重要的某些复合脂质。
Two‐component signal transduction systems (2‐CS) play an important role in bacterial pathogenesis. In the work presented here, we have studied the effects of a mutation in the Mycobacterium tuberculosis (Mtb) PhoPR 2‐CS on the pathogenicity, physiology and global gene expression of this bacterial pathogen. Disruption of PhoPR causes a marked attenuation of growth in macrophages and mice and prevents growth in low‐Mg2+ media. The inability to grow in THP‐1 macrophages can be partially overcome by the addition of excess Mg2+ during infection. Global transcription assays demonstrate PhoP is a positive transcriptional regulator of several genes, but do not support the hypothesis that the Mtb PhoPR system is sensing Mg2+ starvation, as is the case with the Salmonella typhimurium PhoPQ 2‐CS. The genes that were positively regulated include those found in the pks2 and the msl3 gene clusters that encode enzymes for the biosynthesis of sulphatides and diacyltrehalose and polyacyltrehalose respectively. Complementary biochemical studies, in agreement with recent results from another group, indicate that these complex lipids are also absent from the phoP mutant, and the lack of these components in its cell envelope may indirectly cause the mutant's high‐Mg2+ growth requirement. The experiments reported here provide functional evidence for the PhoPR 2‐CS involvement in Mtb pathogenesis, and they suggest that a major reason for the attenuation observed in the phoP mutant is the absence of certain complex lipids that are known to be important for virulence.