肺炎链球菌表型多样化的分子机制：遗传与表观遗传策略的共同作用

doi:10.3877/cma.j.issn.2095-5820.2016.03.009

肺炎链球菌采取高度的遗传可塑性来产生表型多样性。其遗传可塑性体现在该物种具有高度多变的基因组序列，进而产生不同菌株间包括耐药性、荚膜多糖和表面蛋白的抗原性、菌落形态、致病性等的表型多样性。肺炎链球菌的自然转化介导的从环境中获取外源DNA的能力是使其产生遗传可塑性的主要机制。我们实验室最近的单分子测序研究发现肺炎链球菌能够通过DNA甲基转移酶基因的重组产生具有不同染色体DNA甲基化图案(甲基化谱)的子代细胞，这些表观遗传水平上的可逆性变化进而产生透明菌落与非透明菌落之间的可逆性相转变。产生透明菌落与非透明菌落的肺炎链球菌在宿主上皮细胞的黏附和上呼吸道的定植等致病性相关表型方面存在很大差异。在这篇综述中，我们描述了肺炎链球菌如何利用遗传和表观遗传机制增加其表型多样性，重点总结DNA重组所导致的表观遗传变异与菌落形态相转变在该病原体定植与致病性方面的贡献。

关键词: 肺炎链球菌, DNA重组, 染色体甲基化, 表观遗传转变, 相转变

Streptococcus pneumoniae (S. pneumoniae) uses genetic plasticity to achieve phenotypic diversity. The genetic plasticity is reflected by the highly variable genome sequences of this species, which leads to the variation in drug resistance, antigenicity of capsular polysaccharides and surface proteins, colony morphology, and pathogenicity among different pneumococcal strains. Natural transformation of S. pneumoniae is a major known mechanism behind the genetic plasticity, which is characterized by uptake of the exogenous DNA from the environment. Recent studies from our laboratory have revealed that S. pneumoniae is capable of endogenous DNA recombinations in the DNA methyltransferase genes, thereby generating daughter cells with variable genome methylation patterns (or methylomes). These epigenetic switches lead to pneumococcal reversible phase variation between opaque and transparent colony phenotypes, which are associated with differential capabilities in epithelial adherence and nasopharyngeal colonization. In this review, we describe how S. pneumoniae enhances the phenotypic diversity by the genetic and epigenetic mechanisms with a focus on the impact of DNA inversion-driven epigenetic switch and thereby phase variation on pneumococcal pathogenesis.

Key words: Pneumococcus, DNA inversion, Chromosomal methylation, Epigenetic switch, Phase variation

图1 透射电子显微镜下19F血清型肺炎链球菌菌株ST556的细胞图(×50 000倍）

图2 解剖显微镜下19F血清型肺炎链球菌菌株ST556菌落形态图（×5倍）

图3 肺炎链球菌遗传可塑性机制示意图

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Molecular mechanisms of phenotypic diversification in Streptococcus pneumoniae: the impacts of genetic and epigenetic variations

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Molecular mechanisms of phenotypic diversification in Streptococcus pneumoniae: the impacts of genetic and epigenetic variations