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TBADAPT


Tuberculosis

Effect of Genetic Variation in Mycobacterium Tuberculosis on Vaccine Escape and the Acquisition of Drug Resistance
Framework programme:
6
Call:
3
Project number:
LSHP-CT-2006-037919
EC contribution:
€ 1,794,956.7
Duration:
36 Months
Type:
STREP
Starting date:
December 2006

Keywords: Tuberculosis, drug resistance, BCG vaccination, adaptation, DNA repair, DNA fingerprinting

Summary:

The efficacy of BCG vaccination is doubtful and significant problems with resistance against anti-tuberculosis drugs have emerged. These problems could be fuelled by the selection of more adapted variants of Mycobacterium tuberculosis. This project aims to further the hypothesis on the selection of M.tuberculosis genotypes by the measures used to control the tuberculosis(TB) epidemic, anti-TB treatment and BCG vaccination. This will be carried out to:

  1. Study the dynamics of the population structure of M. tuberculosis in various regions in relation to drug resistance and BCG vaccination
  2. Identify genetic factors affecting bacterial adaptability
  3. Study the virulence of strains of emerging genotypes and the level of BCG protection against these strains in vivo
  4. Gain insights into the adaptation of M. tuberculosis in response to control efforts should allow improved strategies for treatment and control and possibly reveal new targets for intervention.

The sequence of selection followed by adaptation may lead to the selection of particularly adaptable strains. Although potentially a serious threat, detailed knowledge of the adaptation process in M. tuberculosis should ultimately allow these pathways to be targeted. This is because, although the accumulation of mutations is a random and unpredictable process, bacteria have specific mechanisms of repairing mutations in DNA. Thus, inhibition of these pathways should greatly reduce the probability of bacteria escaping selective pressure by becoming resistant to anti-TB drugs or becoming escape variants of BCGinduced immunity.

Background:

TB remains a major public health threat, still emerging in some areas of the world. The major tools to control the TB epidemic are worldwide implementation of the directly observed therapy short course (DOTS) programme and BCG vaccination. The protection offered by the BCG vaccine against lung infection is questioned and at best limited. It is therefore suspected that certain emerging strains may have adapted to evade the current vaccine. Despite the availability of effective treatment, the emergence of bacteriaresistant to the anti-TB drugs used is a constant threat. This reservoir of resistant, infectious, pathogenic and probably highly adaptable strains is likely to spread.

So far, the research on the spread of particular M. tuberculosis strains has been focused on strains of the Beijing genotype family. A recent worldwide survey on the distribution of these strains and their associations with drug resistance, covering data on over 29,000 patients in 35 countries, was finalised (Figure 1). This study showed that the Beijing genotype is emerging and is, sometimes in high levels, associated with drug resistance. These strains have also been associated with vaccine escape. Additionally, genetic changes have been identified in putative mutator genes of these strains. The exact phenotypic consequences of this genetic variation in M. tuberculosis (if any) are unknown but it is predicted that these genes are involved in adaptation of the bacteria in the host.

The sequence of selection followed by adaptation may lead to the selection of particularly adaptable strains. Although potentially a serious threat, detailed knowledge of the adaptation process in M. tuberculosis should ultimately allow these pathways to be targeted. This is because, although the accumulation of mutations is a random and unpredictable process, bacteria have specific mechanisms of repairing mutations in DNA. Thus, inhibition of these pathways should greatly reduce the probability of bacteria escaping selective pressure by becoming resistant to anti-TB drugs or becoming escape variants of BCGinduced immunity.

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