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

ABSTRACT

Objectives

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.

Methods

We curated a large nationwide Mycobacterium tuberculosis (M. tuberculosis) 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.

Result

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 (katG_p.Ser315Thr and katG_p.Ser315Asn) and rifampicin (rpoB_p.Ser450Leu, rpoB_p.His445Tyr, rpoB_p.His445Arg, rpoB_p.His445Asp, and rpoB_p.His445Asn) were more likely to be found in L2 clustered strains. Several putative compensatory mutations in rpoA, rpoC, and katG 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.

Conclusion

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.

KEYWORDS:

• Mycobacterium tuberculosis
• whole genome sequence
• lineage
• multidrug-resistant tuberculosis
• transmission
• phylogeny
• China

Acknowledgments

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors' contribution: YFL and XLK analysed the data and drafted the manuscript. WMS, YML, YYL, WWF, JYY, and CBY commented and revised the manuscript. HCL and YL conceptualized, designed the study, and acquired funding for the present study. All authors approved the publication of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The newly sequenced whole genome dataset of 1,449 M. tuberculosis strains was deposited in the NCBI Bio Project (https://www.ncbi.nlm.nih.gov/sra/), and 1755 other isolates were downloaded from the European Nucleotide Archive repository. Any additional data are available from the corresponding authors upon reasonable request.

Additional information

Funding

This work was supported by the Department of Science & Technology of Shandong Province (CN) [grant number 2007GG30002033], [grant number 2017GSF218052], Natural Science Foundation of Shandong Province (CN) [grant number ZR2020KH013], [grant number ZR2021MH006], and Jinan Science and Technology Bureau (CN) [grant number 201704100].