Evolution and epidemic success of Mycobacterium tuberculosis in eastern China: evidence from a prospective study

Lineage distribution of Mycobacterium tuberculosis (Mtb) isolates is strongly associated with geographically distinct human populations, and its transmission can be further impacted by the bacterial genome. However, the epidemic success of Mtb isolates at an individual level was unknown in eastern China. Knowledge regarding the emergence and transmission of Mtb isolates as well as relevant factors may offer a new solution to curb the spread of the disease. Thus, this study aims to reveal the evolution and epidemic success of Mtb isolates in eastern China.

Of initial 1040 isolates, 997 were retained after removing duplicates and those with insufficient sequencing depth. Of the final samples, 733 (73.52%) were from Zhejiang Province, and 264 (26.48%) were from Shanghai City. Lineage 2 and lineage 4 accounted for 80.44% and 19.56%, with common ancestors dating around 7017 years ago and 6882 years ago, respectively. Sub-lineage L2.2 (80.34%) contributed the majority of total isolates, followed by L4.4 (8.93%) and L4.5 (8.43%). Additionally, 51 (5.12%) isolates were identified to be multidrug-resistant (MDR), of which 21 (29.17%) were pre-extensively drug-resistant (pre-XDR). One clade harboring katG S315T mutation may date back to 65 years ago and subsequently acquired mutations conferring resistance to another five antibiotic drugs. The prevalence of compensatory mutation was the highest in pre-XDR isolates (76.19%), followed by MDR isolates (47.06%) and other drug-resistant isolates (20.60%). Time-scaled haplotypic density analyses suggested comparable success indices between lineage 2 and lineage 4 (P = 0.306), and drug resistance did not significantly promote the transmission of Mtb isolates (P = 0.340). But for pre-XDR isolates, we found a higher success index in those with compensatory mutations (P = 0.025). Mutations under positive selection were found in genes associated with resistance to second-line injectables (whiB6) and drug tolerance (prpR) in both lineage 2 and lineage 4.

Our study demonstrates the population expansion of lineage 2 and lineage 4 in eastern China, with comparable transmission capacity, while accumulation of resistance mutations does not necessarily facilitate the success of Mtb isolates. Compensatory mutations usually accompany drug resistance and significantly contribute to the epidemiological transmission of pre-XDR strains. Prospective molecular surveillance is required to further monitor the emergence and spread of pre-XDR/XDR strains in eastern China.