Genomic analysis of lineage-specific transmission of multidrug resistance tuberculosis in China

We investigated the genetic diversities and lineage-specific transmission dynamics of multidrug-resistant tuberculosis (MDR-TB), with the goal of determining the potential factors driving the MDR epidemics in China. We curated a large nationwide <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) whole genome sequence data set, including 1313 MDR strains. We reconstructed the phylogeny and mapped the transmission networks of MDR-TB across China using Bayesian inference. To identify drug-resistance variants linked to enhanced transmissibility, we employed ordinary least-squares (OLS) regression analysis. The majority of MDR-TB strains in China belong to lineage 2.2.1. Transmission chain analysis has indicated that the repeated and frequent transmission of L2.2.1 plays a central role in the establishment of MDR epidemic in China, but no occurrence of a large predominant MDR outbreak was detected. Using OLS regression, the most common single nucleotide polymorphisms (SNPs) associated with resistance to isoniazid (<i>katG_p.Ser315Thr</i> and <i>katG_p.Ser315Asn</i>) and rifampicin (<i>rpoB_p.Ser450Leu</i>, <i>rpoB_p.His445Tyr</i>, <i>rpoB_p.His445Arg</i>, <i>rpoB_p.His445Asp</i>, and <i>rpoB_p.His445Asn</i>) were more likely to be found in L2 clustered strains. Several putative compensatory mutations in <i>rpoA</i>, <i>rpoC</i>, and <i>katG</i> were significantly associated with clustering. The eastern, central, and southern regions of China had a high level of connectivity for the migration of L2 MDR strains throughout the country. The skyline plot showed distinct population size expansion dynamics for MDR-TB lineages in China. MDR-TB epidemic in China is predominantly driven by the spread of highly transmissible Beijing strains. A range of drug-resistance mutations of L2 MDR-TB strains displayed minimal fitness costs and may facilitate their transmission.