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Sci Rep. 2018 Mar 20;8(1):4910. doi: 10.1038/s41598-018-23337-y.

Comparative whole-genome sequence analysis of Mycobacterium tuberculosis isolated from tuberculous meningitis and pulmonary tuberculosis patients.

Author information

1
Department of Microbiology Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand. kiatichai@kku.ac.th.
2
Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, 40002, Thailand. kiatichai@kku.ac.th.
3
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 119077, Singapore.
4
Duke-NUS Medical School, National University of Singapore, Singapore, 119077, Singapore.
5
Department of Microbiology Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
6
Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, 40002, Thailand.
7
Drug Resistant Tuberculosis Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
8
Bioinformatics and Data Management for Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
9
National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Ministry of Science and Technology, Pathum Thani, 12120, Thailand.
10
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077, Singapore.
11
Genome Institute of Singapore, Singapore, 138672, Singapore.
12
Department of Statistics and Applied Probability, National University of Singapore, Singapore, 119077, Singapore.
13
Life Sciences Institute, National University of Singapore, Singapore, 119077, Singapore.
14
Drug Resistant Tuberculosis Laboratory, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand. angkana.cha@mahidol.ac.th.

Abstract

Tuberculous meningitis (TBM) is a severe form of tuberculosis with a high mortality rate. The factors associated with TBM pathogenesis are still unclear. Using comparative whole-genome sequence analysis we compared Mycobacterium tuberculosis (Mtb) isolates from cerebrospinal fluid of TBM cases (n = 73) with those from sputum of pulmonary tuberculosis (PulTB) patients (n = 220) from Thailand. The aim of this study was to seek genetic variants of Mtb associated with TBM. Regardless of Mtb lineage, we found 242 variants that were common to all TBM isolates. Among these variants, 28 were missense SNPs occurring mainly in the pks genes (involving polyketide synthesis) and the PE/PPE gene. Six lineage-independent SNPs were commonly found in TBM isolates, two of which were missense SNPs in Rv0532 (PE_PGRS6). Structural variant analysis revealed that PulTB isolates had 14 genomic regions containing 2-3-fold greater read depth, indicating higher copy number variants and half of these genes belonged to the PE/PPE gene family. Phylogenetic analysis revealed only two small clusters of TBM clonal isolates without support from epidemiological data. This study reported genetic variants of Mtb commonly found in TBM patients compared to PulTB patients. Variants associated with TBM disease warrant further investigation.

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