Outbreak Strain Of Tuberculosis Research Articles

Recurrent tuberculosis in patients infected with the predominant Mycobacterium tuberculosis outbreak strain in Denmark. New insights gained through whole genome sequencing

ObjectivesRecurrent tuberculosis (TB) is defined by more than one TB episode per patient and is caused by reinfection with a new M. tuberculosis (Mtb) strain or relapse with the previous strain. In Denmark, a major TB outbreak caused by one specific Mtb genotype “DKC2” is ongoing. Of the 892 patients infected with DKC2 between 1992 and 2014, 32 had recurrent TB with 67 TB episodes in total. MethodsThe 32 cases were evaluated in terms of number of single-nucleotide polymorphism (SNP) differences and time between episodes derived from whole-genome sequencing data. ResultsFor four TB cases, the subsequent episodes could be confirmed as relapse and for one case as reinfection. Eight cases with SNP differences <6, theoretically indicating relapse, could be classified as likely reinfections based on phylogenetic analysis in combination with geographical data. Subsequent TB episodes for the remaining 19 cases could not be classified as relapse or reinfection even though they all had a SNP difference of <6 SNPs. ConclusionsIn newer studies, investigating recurrent TB with the use of WGS, the number of SNPs has been used to distinguish between relapse and reinfection. The algorithm proposed for this is not valid in the Danish TB outbreak setting as our findings challenge the interpretation of few SNP differences as representing relapse. However, when including phylogenetic analysis and geographical data in the analysis, classification of 13 of the 32 cases were possible.

Evidence for the critical role of a secondary site rpoB mutation in the compensatory evolution and successful transmission of an MDR tuberculosis outbreak strain.

MDR Mycobacterium tuberculosis clinical strains that cause large outbreaks, particularly among HIV-negative patients, are likely to have undergone the most successful compensatory evolution. Hence, mutations secondary to the acquisition of drug resistance are worthy of consideration in these highly transmissible strains. Here, we assessed the role of a mutation within rpoB, rpoB V615M, secondary to the rifampicin resistance-conferring mutation rpoB S531L, which is associated with a major MDR tuberculosis outbreak strain that evolved in an HIV-negative context in northern Tunisia. Using BCG as a model organism, we engineered strains harbouring either the rpoB S531L mutation alone or the double mutation rpoB S531L, V615M. Individual and competitive in vitro growth assays were performed in order to assess the relative fitness of each BCG mutant. The rpoB V615M mutation was found to be invariably associated with rpoB S531L. Structural analysis mapped rpoB V615M to the same bridge helix region as rpoB compensatory mutations previously described in Salmonella. Compared with the rpoB single-mutant BCG, the double mutant displayed improved growth characteristics and fitness rates equivalent to WT BCG. Strikingly, the rpoB double mutation conferred high-level resistance to rifampicin. Here, we demonstrated the fitness compensatory role of a mutation within rpoB, secondary to the rifampicin resistance mutation rpoB S531L, which is characteristic of an MDR M. tuberculosis major outbreak strain. The finding that this secondary mutation concomitantly increased the resistance level to rifampicin argues for its significant contribution to the successful transmission of the MDR-TB strain.

Four decades of transmission of a multidrug-resistant Mycobacterium tuberculosis outbreak strain.

The rise of drug-resistant strains is a major challenge to containing the tuberculosis (TB) pandemic. Yet, little is known about the extent of resistance in early years of chemotherapy and when transmission of resistant strains on a larger scale became a major public health issue. Here we reconstruct the timeline of the acquisition of antimicrobial resistance during a major ongoing outbreak of multidrug-resistant TB in Argentina. We estimate that the progenitor of the outbreak strain acquired resistance to isoniazid, streptomycin and rifampicin by around 1973, indicating continuous circulation of a multidrug-resistant TB strain for four decades. By around 1979 the strain had acquired additional resistance to three more drugs. Our results indicate that Mycobacterium tuberculosis (Mtb) with extensive resistance profiles circulated 15 years before the outbreak was detected, and about one decade before the earliest documented transmission of Mtb strains with such extensive resistance profiles globally.

Mycobacterium tuberculosis Outbreak Strain of Danish Origin Spreading at Worrying Rates among Greenland-Born Persons in Denmark and Greenland

Transmission of Mycobacterium tuberculosis continues at high rates among Greenland-born persons in Greenland and Denmark, with 203 and 450 notified cases per 10(5) population, respectively, in the year 2010. Here, we document that the predominant M. tuberculosis outbreak strain C2/1112-15 of Danish origin has been transmitted to Greenland-born persons in Denmark and subsequently to Greenland, where it is spreading at worrying rates and adding to the already heavy tuberculosis burden in this population group. It is now clear that the C2/1112-15 strain is able to gain new territories using a new population group as the "vehicle." Thus, it might have the ability to spread even further, considering the potential clinical consequences of strain diversity such as that seen in the widely spread Beijing genotype. The introduction of the predominant M. tuberculosis outbreak strain C2/1112-15 into the Arctic circumpolar region is a worrying tendency which deserves attention. We need to monitor whether this strain already has, or will, spread to other countries.

Genomic Stability over 9 Years of an Isoniazid Resistant Mycobacterium tuberculosis Outbreak Strain in Sweden

In molecular epidemiological studies of drug resistant Mycobacterium tuberculosis (TB) in Sweden a large outbreak of an isoniazid resistant strain was identified, involving 115 patients, mainly from the Horn of Africa. During the outbreak period, the genomic pattern of the outbreak strain has stayed virtually unchanged with regard to drug resistance, IS6110 restriction fragment length polymorphism and spoligotyping patterns. Here we present the complete genome sequence analyses of the index isolate and two isolates sampled nine years after the index case as well as experimental data on the virulence of this outbreak strain. Even though the strain has been present in the community for nine years and passaged between patients at least five times in-between the isolates, we only found four single nucleotide polymorphisms in one of the later isolates and a small (4 amino acids) deletion in the other compared to the index isolate. In contrast to many other evolutionarily successful outbreak lineages (e.g. the Beijing lineage) this outbreak strain appears to be genetically very stable yet evolutionarily successful in a low endemic country such as Sweden. These findings further illustrate that the rate of genomic variation in TB can be highly strain dependent, something that can have important implications for epidemiological studies as well as development of resistance.