Highly lethal strain cluster of the Mycobacterium tuberculosis Beijing genotype endemically prevalent in Buryatia, Russia

Two highly-drug resistant clusters of the ancient sublineage of <i>M. tuberculosis</i> Beijing genotype were recently described as emerging in Asian part of Russia. We aimed to analyze their pathogenic properties in vivo. The virulence and lethality of strains were studied in C57BL/6 mouse model. Two clinical MDR isolates belonged to the early ancient Beijing sublineage. Strain 396 had intact RD181 and Mlva 14717-15. Strain 6691 had RD181 deletion and Mlva 1071-32. Strain H37Rv served as reference. Whole genome sequencing (WGS) was done on HiSeq platform. Three tested&nbsp;strains&nbsp;demonstrated different virulence patterns in mice, strain 396 being the most lethal. The 396-infected mice group showed significantly higher mortality, more weight loss, higher bacterial load and more severe lesions in lungs than the other two groups.&nbsp;This strain was even more lethal than notorious Russian epidemic strain Beijing B0/W148. WGS-based analysis revealed SNPs specific for the 14717-15-cluster (that includes strain 396) in 40 genes, including <i>PPE18</i> known to be related to immune evasion and <i>mmpS3</i>, <i>pks7</i> and <i>fadE17</i> likely involved in mycobacterial adaptation. To conclude, strain 6691 belongs to the 1071-32-cluster relatively widespread across former Soviet Union but overall low prevalent; this follows a classical assumption that multiple resistance mutations reduce fitness and transmissibility. In contrast, highly lethal strain 396 represents a Beijing clone 14717-15 endemically prevalent only in Buryatia, Far East, which may be due to its specific highly pathogenic properties and long-term adaptation to the indigenous population. Supported by Russian Science Foundation (grant 19-14-00013).