Saw Seow Hoon, Tan Joon Liang, Chan Xin Yue, Chan Kok Gan, Ngeow Yun Fong
Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Malaysia.
Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, Perak, Malaysia.
PeerJ. 2016 Sep 21;4:e2484. doi: 10.7717/peerj.2484. eCollection 2016.
Meningitis is a major cause of mortality in tuberculosis (TB). It is not clear what factors promote central nervous system invasion and pathology but it has been reported that certain strains of Mycobacterium tuberculosis (Mtb) might have genetic traits associated with neurotropism.
In this study, we generated whole genome sequences of eight clinical strains of Mtb that were isolated from the cerebrospinal fluid (CSF) of patients presenting with tuberculous meningitis (TBM) in Malaysia, and compared them to the genomes of H37Rv and other respiratory Mtb genomes either downloaded from public databases or extracted from local sputum isolates. We aimed to find genomic features that might be distinctly different between CSF-derived and respiratory Mtb.
Genome-wide comparisons revealed rearrangements (translocations, inversions, insertions and deletions) and non-synonymous SNPs in our CSF-derived strains that were not observed in the respiratory Mtb genomes used for comparison. These rearranged segments were rich in genes for PE (proline-glutamate)/PPE (proline-proline-glutamate), transcriptional and membrane proteins. Similarly, most of the ns SNPs common in CSF strains were noted in genes encoding PE/PPE proteins. Protein globularity differences were observed among mycobacteria from CSF and respiratory sources and in proteins previously reported to be associated with TB meningitis. Transcription factors and other transcription regulators featured prominently in these proteins. Homologs of proteins associated with Streptococcus pneumoniae meningitis and Neisseria meningitidis virulence were identified in neuropathogenic as well as respiratory mycobacterial spp. examined in this study.
The occurrence of in silico genetic differences in CSF-derived but not respiratory Mtb suggests their possible involvement in the pathogenesis of TBM. However, overall findings in this comparative analysis support the postulation that TB meningeal infection is more likely to be related to the expression of multiple virulence factors on interaction with host defences than to CNS tropism associated with specific genetic traits.
脑膜炎是结核病（TB）致死的主要原因。目前尚不清楚哪些因素会促进中枢神经系统的侵袭和病变，但有报道称某些结核分枝杆菌（Mtb）菌株可能具有与嗜神经特性相关的遗传特征。
在本研究中，我们对从马来西亚结核性脑膜炎（TBM）患者脑脊液（CSF）中分离出的8株Mtb临床菌株进行了全基因组测序，并将其与从公共数据库下载或从当地痰液分离物中提取的H37Rv及其他呼吸道Mtb基因组进行比较。我们旨在寻找CSF来源的Mtb与呼吸道Mtb之间可能存在明显差异的基因组特征。
全基因组比较显示，我们CSF来源的菌株中存在重排（易位、倒位、插入和缺失）和非同义单核苷酸多态性（nsSNPs），而用于比较的呼吸道Mtb基因组中未观察到这些情况。这些重排片段富含PE（脯氨酸 - 谷氨酸）/PPE（脯氨酸 - 脯氨酸 - 谷氨酸）、转录和膜蛋白相关基因。同样，CSF菌株中常见的大多数nsSNPs存在于编码PE/PPE蛋白的基因中。在CSF和呼吸道来源的分枝杆菌以及先前报道与结核性脑膜炎相关的蛋白质中观察到了蛋白质球状性差异。转录因子和其他转录调节因子在这些蛋白质中显著富集。在本研究中检测的神经致病性以及呼吸道分枝杆菌属中鉴定出了与肺炎链球菌脑膜炎和脑膜炎奈瑟菌毒力相关的蛋白质同源物。
CSF来源而非呼吸道Mtb中存在的计算机模拟遗传差异表明它们可能参与了TBM的发病机制。然而，该比较分析的总体结果支持这样的推测，即结核性脑膜感染更可能与多种毒力因子在与宿主防御相互作用时的表达有关，而不是与特定遗传特征相关的中枢神经系统嗜性有关。
