AUTHOR=Hou Yawei , Li Yifan , Tao Ningning , Kong Xianglong , Li Yameng , Liu Yao , Li Huaichen , Wang Zhenguo 

TITLE=Toxin-antitoxin system gene mutations driving Mycobacterium tuberculosis transmission revealed by whole genome sequencing

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1398886

DOI=10.3389/fmicb.2024.1398886

ISSN=1664-302X

ABSTRACT=<sec id="sec1"><title>Background</title><p>The toxin-antitoxin (TA) system plays a vital role in the virulence and pathogenicity of <italic>Mycobacterium tuberculosis</italic> (<italic>M. tuberculosis</italic>). However, the regulatory mechanisms and the impact of gene mutations on <italic>M. tuberculosis</italic> transmission remain poorly understood.</p></sec><sec id="sec2"><title>Objective</title><p>To investigate the influence of gene mutations in the toxin-antitoxin system on <italic>M. tuberculosis</italic> transmission dynamics.</p></sec><sec id="sec3"><title>Method</title><p>We performed whole-genome sequencing on the analyzed strains of <italic>M. tuberculosis</italic>. The genes associated with the toxin-antitoxin system were obtained from the National Center for Biotechnology Information (NCBI) Gene database. Mutations correlating with enhanced transmission within the genes were identified by using random forest, gradient boosting decision tree, and generalized linear mixed models.</p></sec><sec id="sec4"><title>Results</title><p>A total of 13,518 <italic>M. tuberculosis</italic> isolates were analyzed, with 42.29% (<italic>n</italic> = 5,717) found to be part of genomic clusters. Lineage 4 accounted for the majority of isolates (<italic>n</italic> = 6488, 48%), followed by lineage 2 (<italic>n</italic> = 5133, 37.97%). 23 single nucleotide polymorphisms (SNPs) showed a positive correlation with clustering, including <italic>vapB1</italic> G34A, <italic>vapB24</italic> A76C, <italic>vapB2</italic> T171C, <italic>mazF2</italic> C85T, <italic>mazE2</italic> G104A, <italic>vapB31</italic> T112C, <italic>relB</italic> T226A, <italic>vapB11</italic> C54T, <italic>mazE5</italic> T344C, <italic>vapB14</italic> A29G, <italic>parE1</italic> (C103T, C88T), and <italic>parD1</italic> C134T. Six SNPs, including <italic>vapB6</italic> A29C, <italic>vapB31</italic> T112C, <italic>parD1</italic> C134T, <italic>vapB37</italic> G205C, <italic>Rv2653c</italic> A80C, and <italic>vapB2</italic>2 C167T, were associated with transmission clades across different countries. Notably, our findings highlighted the positive association of <italic>vapB6</italic> A29C, <italic>vapB31</italic> T112C, <italic>parD1</italic> C134T, <italic>vapB37</italic> G205C, <italic>vapB1</italic>9 C188T, and <italic>Rv2653c</italic> A80C with transmission clades across diverse regions. Furthermore, our analysis identified 32 SNPs that exhibited significant associations with clade size.</p></sec><sec id="sec5"><title>Conclusion</title><p>Our study presents potential associations between mutations in genes related to the toxin-antitoxin system and the transmission dynamics of <italic>M. tuberculosis</italic>. However, it is important to acknowledge the presence of confounding factors and limitations in our study. Further research is required to establish causation and assess the functional significance of these mutations. These findings provide a foundation for future investigations and the formulation of strategies aimed at controlling TB transmission.</p></sec>