High Sequence Variability of the ppE18 Gene of Clinical Mycobacterium tuberculosis Complex Strains Potentially Impacts Effectivity of Vaccine Candidate M72/AS01E.
High Sequence Variability of the ppE18 Gene of Clinical Mycobacterium tuberculosis Complex Strains Potentially Impacts Effectivity of Vaccine Candidate M72/AS01E.
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DOI：
10.1371/journal.pone.0152200
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Niemann S
中科院分区：
文献类型：
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作者：
Homolka S;Ubben T;Niemann S
迫切需要开发一种有效的疫苗来抗击结核病，结核病仍然是世界范围内单一传染病致死的主要原因。M72/AS01E是很有希望的候选疫苗之一，由Rv0125和Rv1196编码的两个蛋白亚基PepA和PPE18组成。然而，初步数据表明，临床结核分枝杆菌复合体(MTBC)菌株之间存在很高的序列变异性，这可能会对疫苗效力产生影响。为了进一步研究这一发现，我们在一个具有良好特征的参考集合中测定了ppE18序列的可变性，该参考集合来自23个代表全球MTBC多样性的系统发育谱系中的71个MTBC菌株。总共检测到100个序列变异，包括96个单核苷酸多态(SNPs)、3个插入和1个缺失，导致141个可变位分布在整个基因上。大多数检测到的SNP是非同义的(n=68对n=28)。来自动物适应谱系的菌株，如牛分枝杆菌，比人类病原体如结核分枝杆菌Haarlem显示出显著更高的多样性。可以确定不同谱系以及系统发育中更深层次分支的SNP模式。我们的研究结果表明，即使在PPE基因中通常高度保守的N-末端结构域，ppE18基因也具有高度的变异性。由于N-末端区域与TLR2受体相互作用，诱导保护性抗炎免疫反应，遗传异质性对疫苗效率有潜在影响，但这一点还有待进一步研究。
The development of an effective vaccine is urgently needed to fight tuberculosis (TB) which is still the leading cause of death from a single infectious agent worldwide. One of the promising vaccine candidates M72/AS01E consists of two proteins subunits PepA and PPE18 coded by Rv0125 and Rv1196. However, preliminary data indicate a high level of sequence variability among clinical Mycobacterium tuberculosis complex (MTBC) strains that might have an impact on the vaccine efficacy. To further investigate this finding, we determined ppE18 sequence variability in a well-characterized reference collection of 71 MTBC strains from 23 phylogenetic lineages representing the global MTBC diversity. In total, 100 sequence variations consisting of 96 single nucleotide polymorphisms (SNPs), three insertions and one deletion were detected resulting in 141 variable positions distributed over the entire gene. The majority of SNPs detected were non-synonymous (n = 68 vs. n = 28 synonymous). Strains from animal adapted lineages, e.g., M. bovis, showed a significant higher diversity than the human pathogens such as M. tuberculosis Haarlem. SNP patterns specific for different lineages as well as for deeper branches in the phylogeny could be identified. The results of our study demonstrate a high variability of the ppE18 gene even in the N-terminal domains that is normally highly conserved in ppe genes. As the N-terminal region interacts with TLR2 receptor inducing a protective anti-inflammatory immune response, genetic heterogeneity has a potential impact on the vaccine efficiency, however, this has to be investigated in future studies.