Genomic evidence supporting the clonal expansion of extensively drug-resistant tuberculosis bacteria belonging to a rare proto - Beijing genotype

Abstract

Tuberculosis disease (TB), caused by Mycobacterium tuberculosis , is a major public health issue in Thailand. The high prevalence of modern Beijing (Lineage 2.2.1) strains has been associated with multi- and extensively drug-resistant infections (MDR-, XDR-TB), complicating disease control. The impact of rarer proto-Beijing (L2.1) strains is less clear. In our study of thirty-seven L2.1 clinical isolates spanning thirteen years, we found a high prevalence of XDR-TB cases (32.4%). With ≤ 12 pairwise SNP distances, 43.2% of L2.1 patients belong to MDR-TB or XDR-TB transmission clusters suggesting a high level of clonal expansion across four Thai provinces. All XDR-TB (100%) were likely due to transmission rather than inadequate treatment. We found a 47 mutation signature and a partial deletion of the fadD14 gene in the circulating XDR-TB cluster, which can be used for surveillance of this rare and resilient M. tuberculosis strain-type that is causing increasing health burden. We also detected three novel deletion positions, a deletion of 1285 bp within desA3 (Rv3230c) , large deletions in the plcB, plcA, and ppe38 gene which may play a role in the virulence, pathogenesis or evolution of the L2.1 strain-type.

Connection between two historical tuberculosis outbreak sites in Japan, Honshu, by a new ancestral Mycobacterium tuberculosis L2 sublineage

“…L2.1 was described mainly in south-China, particularly in the Guangxi province and could be as ancient as 30 000 years old, having co-evolved with east Asian populations [ 8 ]. Among its characteristics, it harbours the RD105 deletion but not RD207 [ 32 ]. Rare L2.1 isolates were shown to have become ultra-drug resistant [ 32 ].…”

“…The large databases built with WGS data allow to develop a precise and comprehensive knowledge of L2 diversity [ 4 , 26 , 31 , 37 ]. Computational genomics now allows to study in-depth both the global and the local L2 history [ 6 , 24 , 26 , 32 , 35 , 38 – 42 ]. The evolutionary history of L2 isolates is still debated as is their precise dating of emergence and their geographical origin [ 26 , 34 ].…”

Connection between two historical tuberculosis outbreak sites in Japan, Honshu, due to a new ancestral L2 sublineage

“…L2.1 is known as "Proto-Beijing" and is found mainly in Southern China, particularly in Guangxi province [27]. Among the major characteristics is the fact that it possesses the L2 characterizing RD105 deletion but not RD207 [28]. Recently a rare L2.1 clone was shown to have become ultra-drug resistant [28].…”

“…Among the major characteristics is the fact that it possesses the L2 characterizing RD105 deletion but not RD207 [28]. Recently a rare L2.1 clone was shown to have become ultra-drug resistant [28].…”

“…Bmyc6 or Bmyc26) remained unclusterized based on the most recent classification scheme [31]. This suggests that some improvements in the Shitikov L2 classification scheme are possible; meanwhile other L2 sublineages were described such as in Thailand or Japan, and their history should also be linked to the global L2 history by performing comparative genomics [6,23,28,32,[38][39][40][41][42].…”