Transmission dynamics variability of lineage 2 Mycobacterium tuberculosis strains in Kobe, Japan, determined using population-based whole-genome sequencing analysis.

Currently, tuberculosis (TB) in Japan is highly prevalent among elderly patients who were born during a time when TB was highly prevalent. Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is the predominant strain in the country. Moreover, the proportion of foreign-born patients with TB has been increasing. This epidemiological situation in Japan motivated us to explore the heterogeneity in transmission dynamics among the sublineages of Mtb L2 within this aging population. For this purpose, we conducted a population-based whole genome sequencing analysis of 550 Mtb strains in Kobe, Japan, and employed pairwise single nucleotide polymorphism (SNP) distance clustering and terminal branch length (TBL) distribution analysis to assess Mtb transmission. The genomic clustering rate with a threshold of ≤5 SNPs was significantly lower in elderly patients aged 70 years or higher than in non-elderly patients. The elderly patient group showed significantly longer TBL than the non-elderly group. These results supported the notion that reactivation of distant infection is a major driving force for the high incidence of TB in elderly individuals. The age group distribution and frequency of lineages/sublineages were found to significantly differ between foreign-born and Japan-born patients. The increased proportion of foreign-born patients might have resulted in more strain diversity in Japan. The L2.2.A sublineage demonstrated a significant association with elderly patients and exhibited lower transmission rates, which indicate to be prone to reactivate from long-term latency. In contrast, L2.2.Modern, showed a strong association with younger and foreign-born patients. This sublineage showed a high genomic cluster rate, suggesting its high transmissibility. The other three major sublineages, namely L2.2.AA2, L2.2.AA3.1, and L2.2.AA3.2, exhibited a consistent increase in cluster rates across varying SNP thresholds, indicating their relatively recent emergence as endemic sublineages in Japan. In conclusion, this study highlights distinct differences in the transmission dynamics of L2 sublineages within an aging society.