Disclosure of Selective Advantages in the “modern” Sublineage of the Mycobacterium tuberculosis Beijing Genotype Family by Quantitative Proteomics

Abstract

The Mycobacterium tuberculosis Beijing genotype, consisting of the more ancient (atypical) and modern (typical) emerging sublineage, is one of the most prevalent and genetically conserved genotype families and has often been associated with multidrug resistance. In this study, we employed a 2D-LC-FTICR MS approach, combined with dimethylation of tryptic peptides, to systematically compare protein abundance levels of ancient and modern Beijing strains and identify differences that could be associated with successful spread of the modern sublineage. The data is available via ProteomeXchange using the identifier PXD000931. Despite the highly uniform protein abundance ratios in both sublineages, we identified four proteins as differentially regulated between both sublineages, which could explain the apparent increased adaptation of the modern Beijing strains. These proteins are; Rv0450c/ MmpL4, Rv1269c, Rv3137, and Rv3283/sseA. Transcriptional and functional analysis of these proteins in a large cohort of 29 Beijing strains showed that the mRNA levels of Rv0450c/MmpL4 are significantly higher in modern Beijing strains, whereas we also provide evidence that Rv3283/ sseA is less abundant in the modern Beijing sublineage. Our findings provide a possible explanation for the increased virulence and success of the modern Beijing sublineage. In addition, in the established dataset of 1817 proteins, we demonstrate the pre-existence of several, possibly unique, antibiotic efflux pumps in the proteome of the Beijing strains. This may reflect an increased ability of Beijing strains to escape exposure to antituberculosis drugs. Molecular & Cellular

A Comparison of the Sensititre MycoTB Plate, the Bactec MGIT 960, and a Microarray-Based Molecular Assay for the Detection of Drug Resistance in Clinical Mycobacterium tuberculosis Isolates in Moscow, Russia

“…The identification of the MTB lineage is believed to have a clinical impact due to the association of some lineages, particularly modern Beijing, with virulence [46], transmission [47], drug tolerance [48] and adaptation [49]. The Beijing lineage was identified in 77% of the isolates, including the “successful” B0/W148 sublineage (21%) [50].…”

Systems proteomics approaches to study bacterial pathogens: application to Mycobacterium tuberculosis

“…SseA, a predicted thiol-oxidoreductase, together with SodA and DoxX constitute a membrane-associated oxidoreductase complex (MRC) and lack of any MRC subunit results in the defective recycling of mycothiol as a functional analog of glutathione [48,49]. The low level of SseA in the modern Beijing strains most likely results in increased DNA oxidation damage which explains the higher rate of mutation and accelerated acquisition of drug resistance compared to more ancient strains [50]. Up-regulation of enzymes responsible for long-chain fatty acid biosynthesis and HsaA implicated in steroid degradation and down-regulation of long-chain fatty acid degrading enzymes have been observed in Beijing B0/W148 strains in compared to the reference strain termed H37Rv [49].…”

Proteomics for the Investigation of Mycobacteria

“…Meanwhile, the content of proteins Hsp65 (Rv0440), Pst1 (Rv0934), and Rv1886c, which are basic antigens whose reduced production may contribute to the avoidance of the host’s immune response by mycobacteria [61, 62], was decreased. Furthermore, proteins of the efflux pumps Rv0341, Rv2688c, and Rv3728 were found only in the Beijing strains [35]. …”