Single nucleotide polymorphisms may explain the contrasting phenotypes of two variants of a multidrug-resistant Mycobacterium tuberculosis strain

Abstract

Globally, about 4.5% of new tuberculosis (TB) cases are multi-drug-resistant (MDR), i.e. resistant to the two most powerful first-line anti-TB drugs. Indeed, 480,000 people developed MDR-TB in 2015 and 190,000 people died because of MDR-TB. The MDR Mycobacterium tuberculosis M family, which belongs to the Haarlem lineage, is highly prosperous in Argentina and capable of building up further drug resistance without impairing its ability to spread. In this study, we sequenced the whole genomes of a highly prosperous M-family strain (Mp) and its contemporary variant, strain 410, which produced only one recorded tuberculosis case in the last two decades. Previous reports have demonstrated that Mp induced dysfunctional CD8 cytotoxic T cell activity, suggesting that this strain has the ability to evade the immune response against M. tuberculosis. Comparative analysis of Mp and 410 genomes revealed non-synonymous polymorphisms in eleven genes and five intergenic regions with polymorphisms between both strains. Some of these genes and promoter regions are involved in the metabolism of cell wall components, others in drug resistance and a SNP in Rv1861, a gene encoding a putative transglycosylase that produces a truncated protein in Mp. The mutation in Rv3787c, a putative S-adenosyl-l-methionine-dependent methyltransferase, is conserved in all of the other prosperous M strains here analysed and absent in non-prosperous M strains. Remarkably, three polymorphic promoter regions displayed differential transcriptional activity between Mp and 410. We speculate that the observed mutations/polymorphisms are associated with the reported higher capacity of Mp for modulating the host's immune response.

A Phenotypic Characterization of Two Isolates of a Multidrug-Resistant Outbreak Strain of Mycobacterium tuberculosis with Opposite Epidemiological Fitness

“…One of the most accumulated proteins in the strain 410 was IdsA. This result is in accordance with the results of our previous study, in which this protein, a geranylgeranyl pyrophosphate synthetase protein likely involved in lipid biosynthesis, showed higher levels of transcription in 410 than in Mp [9]. The strain 410 also accumulated three proteins from the DevR regulon (Rv0569, Rv2031c, and Rv2007c), two proteins of unknown functions (Rv3221c and Rv2081c), a GCN5-related N-acetyltransferase (Eis, Rv2416c), and a putative ribonuclease E (Rv2444c).…”

“…In our study, the high level of genomic conservation between the strains Mp and 410 [9] was translated to similar proteomes for the Mp and 410 strains. Only 12 proteins showed higher accumulation (FC > 2) in one strain relative to the other.…”

“…Mp is also resistant to kanamycin and ethambutol. Both strains are genetically close, since they have similar molecular markers [9].…”

“…Recently, we searched for all polymorphisms occurring between an early representative of the M prototype strain, hereafter named Mp, and its contemporary variant 410. In that study, polymorphisms located in 11 proteins and five intergenic regions were identified [9]. Some of these polymorphisms were located in proteins or promoter regions involved in the metabolism of cell wall components, whereas others occurred in proteins associated with drug resistance [9].…”

“…In that study, polymorphisms located in 11 proteins and five intergenic regions were identified [9]. Some of these polymorphisms were located in proteins or promoter regions involved in the metabolism of cell wall components, whereas others occurred in proteins associated with drug resistance [9]. Some progress has been made in the understanding of the molecular mechanisms that determine the epidemiological success of certain M. tuberculosis lineages and of the M family in particular.…”