MTB VARIATION

High throughput sequencing to reveal the causes and consequences of Mycobacterium tuberculosis genomic variation

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 Obiettivo del progetto (Objective)

'Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans, is estimated to infect one third of the human population leading to circa two million deaths a year. While many work has been done onto the socio-economic and host factors affecting the different outcomes of the disease, little is still known about the possible influence of Mycobacterium tuberculosis strain variation. Compare to other bacteria, Mtb has very low polymorphism which have prevented until now a detailed study of the evolutionary forces behind this pathogen. With the advent of next-generation sequencing this gap in our knowledge on the population genetics of Mtb with respect other bacteria is starting to close. This project will be aimed to analyze 100 Mtb strains currently being sequenced by the Sanger institute using Illumina technology which added to our previous panel of 30 strains already generated will allow detail population genetics and evolutionary studies with an special focus on the evolution of known Mtb antigens. Collaborations with laboratories with expertise in immunology, transcriptomics and molecular epidemiology will allow us to put in context the consequences of the Mtb genomic variation found in this study.'

Introduzione (Teaser)

Mycobacterium tuberculosis has two faces: it can either cause acute or chronic disease. Using state-of-the-art sequencing methods, European researchers attributed this phenomenon to genomic diversity.

Descrizione progetto (Article)

Tuberculosis remains one of the leading causes of mortality worldwide, accounting for approximately two million deaths per year. Despite extensive research, the only means of decreasing disease risk is the BCG vaccine, which confers protection for a limited time only.

M. tuberculosis is genetically diverse and different bacterial lineages are associated with varied clinical and epidemiological manifestations of the disease. Understanding the determinants of bacterial evolution and genomic diversity could have important implications for the design of future therapeutic interventions.

The EU-funded MTB VARIATION project set out to investigate the evolution of M. tuberculosis and its characteristics. In this context, scientists sequenced the genome of nearly 260 different genetic bacterial isolates collected from various parts of the world. Comparative genomic analysis unravelled more than thirty thousand single nucleotide polymorphisms of putative therapeutic potential.

Evolutionary analyses of the different bacterial lineages revealed a perfect correlation among bacterial and human population migration and dynamics. Also, the success of the human population during the Neolithic period seemed to support the success of tuberculosis spread and its global domination.

Interestingly, researchers found that M. tuberculosis also managed to survive in small groups of hunt-gatherers probably through domination of less virulent strains. When host numbers were not a limitation, M. tuberculosis probably switched to more virulent strains. As a result, the identification of the genetic determinants of this transition may provide the answer to the eradication of tuberculosis.

Project results provide unprecedented insight into the genomic diversity and evolution of M. tuberculosis. Future studies on selective and non-selective environmental pressure could be exploited to further comprehend the virulence and epidemiology of this serious pathogen.