Abstract
Denmark, a tuberculosis low burden country, still experiences significant active Mycobacterium tuberculosis (Mtb) transmission, especially with one specific genotype named Cluster 2/1112–15 (C2), the most prevalent lineage in Scandinavia. In addition to environmental factors, antibiotic resistance, and human genetics, there is increasing evidence that Mtb strain variation plays a role for the outcome of infection and disease. In this study, we explore the reasons for the success of the C2 genotype by analysing strain specific polymorphisms identified through whole genome sequencing of all C2 isolates identified in Denmark between 1992 and 2014 (n = 952), and the demographic distribution of C2. Of 234 non-synonymous (NS) monomorphic SNPs found in C2 in comparison with Mtb reference strain H37Rv, 23 were in genes previously reported to be involved in Mtb virulence. Of these 23 SNPs, three were specific for C2 including a NS mutation in a gene associated with hyper-virulence. We show that the genotype is readily transmitted to different ethnicities and is also found outside Denmark. Our data suggest that strain specific virulence factor variations are important for the success of the C2 genotype. These factors, likely in combination with poor TB control, seem to be the main drivers of C2 success.
Highlights
There is increasing evidence that, in addition to environmental factors[1], drug resistance[2] and human genetics[3], strain variation in members of the Mycobacterium tuberculosis Complex (MTBC) plays a key role in the outcome of tuberculosis (TB) infection and disease[4,5]
We have previously characterized the Cluster 2/1112–15 (C2) outbreak using whole genome sequencing (WGS) on a sparse time-series consisting of 115 isolates and shown that it was a clonal outbreak belonging to MTBC lineage 4.8, with 2 discernible phylogenetic clades, a major and a minor, and a most common recent ancestor dating back to 1959, pointing to its introduction into Denmark sometime after the Second World War[11]
In order to investigate the potential biological backgrounds for the success of this Mycobacterium tuberculosis (Mtb) strain, we extend our WGS analysis to all available C2 isolates identified between 1992 and 2014 to pinpoint all universally preserved mutations to allow a detailed analysis of all C2-specific polymorphisms
Summary
There is increasing evidence that, in addition to environmental factors[1], drug resistance[2] and human genetics[3], strain variation in members of the Mycobacterium tuberculosis Complex (MTBC) plays a key role in the outcome of tuberculosis (TB) infection and disease[4,5]. Molecular epidemiology studies have demonstrated a diverse Mycobacterium tuberculosis (Mtb) population structure and the existence of specific dominant clonal lineages with epidemic behaviour. This implies that some strains may have acquired functional advantages (over others) in their ability to transmit and cause disease[6]. In Denmark, one specific clonal strain has increased dramatically This outbreak strain, “Cluster 2/1112–15” (hereafter, just C2), was first identified in 1992 in 8 patients. In order to investigate the potential biological backgrounds for the success of this Mtb strain, we extend our WGS analysis to all available C2 isolates identified between 1992 and 2014 to pinpoint all universally preserved mutations to allow a detailed analysis of all C2-specific polymorphisms. As the definition of virulence is still widely discussed, we use the terms virulence and success interchangeably
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