Mycobacterium tuberculosis
World Tuberculosis Day on 24 March recognises the date in 1882 when Dr Robert Koch announced his discovery of Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB). In celebration of this, we are excited to present a collection of recently published papers on M. tuberculosis.
Collection Contents
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Genome-based transmission modelling separates imported tuberculosis from recent transmission within an immigrant population
In many countries the incidence of tuberculosis (TB) is low and is largely shaped by immigrant populations from high-burden countries. This is the case in Norway, where more than 80 % of TB cases are found among immigrants from high-incidence countries. A variable latent period, low rates of evolution and structured social networks make separating import from within-border transmission a major conundrum to TB control efforts in many low-incidence countries. Clinical Mycobacterium tuberculosis isolates belonging to an unusually large genotype cluster associated with people born in the Horn of Africa have been identified in Norway over the last two decades. We modelled transmission based on whole-genome sequence data to estimate infection times for individual patients. By contrasting these estimates with time of arrival in Norway, we estimate on a case-by-case basis whether patients were likely to have been infected before or after arrival. Independent import was responsible for the majority of cases, but we estimate that about one-quarter of the patients had contracted TB in Norway. This study illuminates the transmission dynamics within an immigrant community. Our approach is broadly applicable to many settings where TB control programmes can benefit from understanding when and where patients acquired TB.
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Growth characteristics of liquid cultures increase the reliability of presumptive identification of Mycobacterium tuberculosis complex
We evaluated the microscopic and macroscopic characteristics of mycobacteria growth indicator tube (MGIT) cultures for the presumptive identification of the Mycobacterium tuberculosis complex (MTBC) and assessed the reliability of this strategy for correctly directing isolates to drug susceptibility testing (DST) or species identification. A total of 1526 isolates of mycobacteria received at the Instituto Adolfo Lutz were prospectively subjected to presumptive identification by the observation of growth characteristics along with cord formation detection via microscopy. The presumptive identification showed a sensitivity, specificity and accuracy of 98.8, 92.5 and 97.9 %, respectively. Macroscopic analysis of MTBC isolates that would have been erroneously classified as non-tuberculous mycobacteria based solely on microscopic morphology enabled us to direct them rapidly to DST, representing a substantial gain to patients. In conclusion, the growth characteristics of mycobacteria in MGIT, when considered along with cord formation, increased the reliability of the presumptive identification, which has a great impact on the laboratory budget and turnaround times.
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Global mapping of MtrA-binding sites links MtrA to regulation of its targets in Mycobacterium tuberculosis
Mycobacterium tuberculosis employs two-component systems (TCSs) for survival within its host. The TCS MtrAB is conserved among mycobacteria. The response regulator MtrA is essential in M. tuberculosis. The genome-wide chromatin immunoprecipitation (ChIP) sequencing performed in this study suggested that MtrA binds upstream of at least 45 genes of M. tuberculosis, including those involved in cell wall remodelling, stress responses, persistence and regulation of transcription. It binds to the promoter regions and regulates the peptidoglycan hydrolases rpfA and rpfC, which are required for resuscitation from dormancy. It also regulates the expression of whiB4, a critical regulator of the oxidative stress response, and relF, one-half of the toxin–antitoxin locus relFG. We have identified a new consensus 9 bp loose motif for MtrA binding. Mutational changes in the consensus sequence greatly reduced the binding of MtrA to its newly identified targets. Importantly, we observed that overexpression of a gain-of-function mutant, MtrAY102C, enhanced expression of the aforesaid genes in M. tuberculosis isolated from macrophages, whereas expression of each of these targets was lower in M. tuberculosis overexpressing a phosphorylation-defective mutant, MtrAD56N. This result suggests that phosphorylated MtrA (MtrA-P) is required for the expression of its targets in macrophages. Our data have uncovered new MtrA targets that suggest that MtrA is required for a transcriptional response that likely enables M. tuberculosis to persist within its host and emerge out of dormancy when the conditions are favourable.
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Guardians of the mycobacterial genome: A review on DNA repair systems in Mycobacterium tuberculosis
More LessThe genomic integrity of Mycobacterium tuberculosis is continuously threatened by the harsh survival conditions inside host macrophages, due to immune and antibiotic stresses. Faithful genome maintenance and repair must be accomplished under stress for the bacillus to survive in the host, necessitating a robust DNA repair system. The importance of DNA repair systems in pathogenesis is well established. Previous examination of the M. tuberculosis genome revealed homologues of almost all the major DNA repair systems, i.e. nucleotide excision repair (NER), base excision repair (BER), homologous recombination (HR) and non-homologous end joining (NHEJ). However, recent developments in the field have pointed to the presence of novel proteins and pathways in mycobacteria. Homologues of archeal mismatch repair proteins were recently reported in mycobacteria, a pathway previously thought to be absent. RecBCD, the major nuclease-helicase enzymes involved in HR in E. coli, were implicated in the single-strand annealing (SSA) pathway. Novel roles of archeo-eukaryotic primase (AEP) polymerases, previously thought to be exclusive to NHEJ, have been reported in BER. Many new proteins with a probable role in DNA repair have also been discovered. It is now realized that the DNA repair systems in M. tuberculosis are highly evolved and have redundant backup mechanisms to mend the damage. This review is an attempt to summarize our current understanding of the DNA repair systems in M. tuberculosis.
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