Jia Xinmiao, Yang Li, Dong Mengxing, Chen Suting, Lv Lingna, Cao Dandan, Fu Jing, Yang Tingting, Zhang Ju, Zhang Xiangli, Shang Yuanyuan, Wang Guirong, Sheng Yongjie, Huang Hairong, Chen Fei
CAS Key Laboratory of Genome Sciences & Information, Beijing Institute of Genomics, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute Beijing, China.
Front Cell Infect Microbiol. 2017 Mar 21;7:88. doi: 10.3389/fcimb.2017.00088. eCollection 2017.
Tuberculosis now exceeds HIV as the top infectious disease cause of mortality, and is caused by the complex (MTBC). MTBC strains have highly conserved genome sequences (similarity >99%) but dramatically different phenotypes. To analyze the relationship between genotype and phenotype, we conducted the comparative genomic analysis on 12 MTBC strains representing different lineages (i.e., ; BCG; ; ; H37Rv; H37Ra, and six clinical isolates). The analysis focused on the three aspects of pathogenicity: host association, virulence, and epitope variations. Host association analysis indicated that eight genes, two enoyl-CoA hydratases, and five PE/PPE family genes were present only in human isolates; these may have roles in host-pathogen interactions. There were 15 SNPs found on virulence factors (including five SNPs in three ESX secretion proteins) only in the Beijing strains, which might be related to their more virulent phenotype. A comparison between the virulent H37Rv and non-virulent H37Ra strains revealed three SNPs that were likely associated with the virulence attenuation of H37Ra: S219L (PhoP), A219E (MazG) and a newly identified I228M (EspK). Additionally, a comparison of animal-associated MTBC strains showed that the deletion of the first four genes (i.e., ), rather than all eight genes of RD1, might play a central role in the virulence attenuation of animal isolates. Finally, by comparing epitopes among MTBC strains, we found that four epitopes were lost only in the Beijing strains; this may render them better capable of evading the human immune system, leading to enhanced virulence. Overall, our comparative genomic analysis of MTBC strains reveals the relationship between the highly conserved genotypes and the diverse phenotypes of MTBC, provides insight into pathogenic mechanisms, and facilitates the development of potential molecular targets for the prevention and treatment of tuberculosis.
结核病现已超过艾滋病毒，成为头号感染性致死病因，由结核分枝杆菌复合群（MTBC）引起。MTBC菌株具有高度保守的基因组序列（相似度>99%），但其表型却有显著差异。为分析基因型与表型之间的关系，我们对代表不同谱系的12株MTBC菌株（即；卡介苗；；；H37Rv；H37Ra，以及6株临床分离株）进行了比较基因组分析。该分析聚焦于致病性的三个方面：宿主关联、毒力和表位变异。宿主关联分析表明，8个基因、2个烯酰辅酶A水合酶和5个PE/PPE家族基因仅存在于人类分离株中；这些基因可能在宿主-病原体相互作用中发挥作用。仅在北京菌株的毒力因子上发现了15个单核苷酸多态性（SNP）（包括3种ESX分泌蛋白中的5个SNP），这可能与其更强的毒力表型有关。毒力强的H37Rv菌株与无毒力的H37Ra菌株比较，发现3个可能与H37Ra毒力减弱相关的SNP：S219L（PhoP）、A219E（MazG）和一个新发现的I228M（EspK）。此外，对与动物相关的MTBC菌株进行比较表明，缺失前4个基因（即），而非RD1的所有8个基因，可能在动物分离株的毒力减弱中起核心作用。最后，通过比较MTBC菌株之间的表位，我们发现4个表位仅在北京菌株中缺失；这可能使它们更能逃避人类免疫系统，从而导致毒力增强。总体而言，我们对MTBC菌株的比较基因组分析揭示了MTBC高度保守基因型与多样表型之间的关系，深入了解了致病机制，并为结核病的预防和治疗提供了潜在分子靶点。
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