Mismatch repair and the regulation of phase variation in Neisseria meningitidis
Mismatch repair and the regulation of phase variation in Neisseria meningitidis
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DOI：
10.1046/j.1365-2958.2001.02408.x
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发表时间：
2001-05-01
影响因子：
3.6
通讯作者：
Stojiljkovic, I
中科院分区：
文献类型：
--
作者：
Richardson, AR;Stojiljkovic, I
脑膜炎奈瑟菌通过一种称为阶段变异的过程控制参与宿主适应的几种基因的表达。血清群A、B和C的临床分离株之间血红蛋白（Hb）受体的相位变异频率差异很大，范围约为10（-6）至10（-2）cfu（-1）。相位变化的频率是特定菌株的遗传性状，因为两个不相关的Hb受体hpuAB和hmbR在给定的分离株内以相似的频率相位变化。根据这些频率，6株奈瑟氏球菌临床分离株可分为3个不同的类别：慢、中和快。相变化频率的增加，伴随着高速率的自发突变，利福平和萘啶酸耐药性在一个介质和一个快速应变。其余三种培养基菌株显示相位变异水平升高，但总体突变性未增加，因为它们具有低的耐药性自发突变率。N.发现脑膜炎在确定临床分离株的总体突变性中起重要作用。失活的错配修复在任何菌株，无论其原始表型，增加突变的快速应变中看到的水平。mutS和mutL的插入失活导致慢应变hmbR开关频率分别增加500倍和250倍。同时，自发的mutS和mutL突变体的频率从慢应变增加20- 30倍的高应变中看到的水平。Dam甲基化的状态与Hb受体的相位变异频率或奈瑟菌菌株的一般突变性均不相关。对扩大的分离株集的分析发现，错配修复缺陷是表现出快速Hb转换和高突变率表型的菌株的遗传基础。总之，相位变化频率的升高伴随着一些N.脑膜炎分离株，包括显示为错配修复缺陷的菌株。其他分离株的进化机制似乎只影响相位可变基因的转换频率，而不伴随自发突变的积累。
Neisseria meningitidis controls the expression of several genes involved in host adaptation by a process known as phase variation. The phase variation frequency of haemoglobin (Hb) receptors among clinical isolates of serogroups A, B and C differed drastically, ranging from approximate to 10(-6) to 10(-2) cfu(-1). Frequencies of phase variation are a genetic trait of a particular strain, as two unlinked Hb receptors, hpuAB and hmbR, phase varied with similar frequencies within a given isolate. Based on these frequencies, six Neisserial clinical isolates could be grouped into three distinct classes; slow, medium and fast. An increase in phase variation frequency was accompanied by high rates of spontaneous mutation to rifampicin and nalidixic acid resistance in one medium and one fast strain. The remaining three medium strains displayed elevated levels of phase variation without increases in overall mutability, as they possessed low rates of spontaneous mutation to drug resistance. The mismatch repair system of N. meningitidis was found to play an important role in determining the overall mutability of the clinical isolates. Inactivation of mismatch repair in any strain, regardless of its original phenotype, increased mutability to a level seen in the fast strain. Insertional inactivation of mutS and mutL in the slow strain led to 500- and 250-fold increases in hmbR switching frequency respectively. Concurrently, the frequency of spontaneous point mutations of mutS and mutL mutants from the slow strain was increased 20- to 30-fold to the level seen in the high strain. The status of Dam methylation did not correlate with either the phase variation frequency of Hb receptors or the general mutability of Neisserial strains. Analysis of an expanded set of isolates identified defects in mismatch repair as the genetic basis for strains displaying both the fast Hb switching and high mutation rate phenotypes. In conclusion, elevated frequencies of phase variation were accompanied by increased overall mutability in some N. meningitidis isolates including strains shown to be mismatch repair defective. Other isolates have evolved mechanisms that seem to affect only the switching frequency of phase-variable genes without an accompanied increased accumulation of spontaneous mutations.