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TBADAPT
Tuberculosis
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
Graphic element Effect of Genetic Variation in Mycobacterium Tuberculosis on Vaccine Escape and the Acquisition of Drug Resistance
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.

Aim:

The objective of the project is to further the hypothesis that the current TB epidemic is fuelled by the selection of more adapted variants of M. tuberculosis by the measures used to control the epidemic. These selection mechanisms will be investigated by studying the population structure of M. tuberculosis in various regions by using DNA fingerprint tools. Trends in the dynamics of the population structure (emerging genotypes) will be identified. The association of the various genotypes with drug resistance or possible vaccine escape will be studied.

Furthermore, the influence of genetic variability among M. tuberculosis strains on the virulence and immune response induced by these strains and the protection of various vaccines against these strains will be studied in a BALB/c mouse model for pulmonary tuberculosis. In addition, the effect of genetic variation, in the M. tuberculosis genome on the mechanisms of bacterial adaptability and response to stress will be studied. This will involve in vitro studies of the phenotypic effect of specific drug resistance and other mutations, with an emphasis on mutations in (putative) DNA repair genes.

Expected results:

The project will obtain insight in the population structure of M. tuberculosis in various areas, including high- and low-TB incidence countries and multidrug resistant (MDR) TB hot-spot regions. Emerging genotypes will be identified and it will be investigated whether the emergence of certain genotypes is associated with BCG vaccination and/or drug resistance.

Comparative in vitro studies of the virulence and immune response induced by representative strains of different M. tuberculosis genotype families will improve the understanding of the mechanisms of success of the major M. tuberculosis strains causing the current worldwide tuberculosis epidemic. The in vitro studies of the effect of drug resistance and DNA repair mutations will enhance the understanding of the impact of these genes on drug resistance acquisition

Potential applications:

Various strain collections will be established, including strains from high MDRTB prevalence countries, strains of well-characterised epidemic M. tuberculosis genotypes, and laboratory mutants with modified DNA repair genes. These strains are likely to be used in further studies.

Characterisation of M. tuberculosis strains that are emerging because they have a higher ability to resist the anti-TB drugs and/or BCG vaccination will contribute to the research on the development of new tuberculosis vaccines. If differences in susceptibility between M. tuberculosis strains to BCG-induced immunity are found this would emphasise that new anti-TB vaccines should be tested for efficacy against a variety of circulating M. tuberculosis strains. If different levels of association with drug resistance or BCG vaccination exist between the closely related strains of a certain genotype this may accelerate the research on the development of drug resistance and the preparation of a new anti-TB vaccine, by studying the (limited) genetic differences between these strains. The study of genetically closely related, more and less successful strains of a certain genotype may thus indirectly aid the development of an effective anti-TB vaccine.

Coordinator:

Kristin Kremer
National Institute of Public Health and the Environment (RIVM)
Mycobacteria Reference Unit
Centre for Infectious Disease Control
P.O. box 1- 3720 BA Bilthoven, The Netherlands
Tel: +31-30-2742720
Fax: +31-30-2744418
E-mail: kristin.kremer@rivm.nl
www.caontb.rivm.nl

Partners:

Principal
Scientific
Participants
Official Address Other Information
2 Richard M. Anthony Royal Tropical Institute (KIT)
Biomedical Research
P.O. box 95001
1090 HA Amsterdam
The Netherlands
Tel: +31-20-5665449
Fax: +31-20-6971841
E-mail: r.anthon@Kit.nl
Website:www.kit.nl
3 Rogelio Hernandez Pando National Institute of Medical Sciences
and Nutrition “Salvador Zubiran” (NIMSN)
Experimental Pathology Section
Department of Pathology
Vasco de Quiroga no. 15, col. seccion XVI
14000 Mexico D.F. - Mexico
Tel: +52-5554870900
Fax: +52-5554853491
Website:www.innsz.mx
4 Gunnar A. Bjune University of Oslo
Department for General Practice
and Community Medicine
Ullevaalsalleen
1130 Blindern / 0317 Oslo
Norway
Tel: +47-22850640
Fax: +47-2285672
Email: g.a.bjune@medisin.uio.no
Website:www.uio.no
5 Afranio L. Kritski Federal University of Rio de Janeiro
Department of Clinical Medicine
Tuberculosis Research Unit
Av. Brigadeiro Trompowsky s/n Ilha do
Fundao-Predio Hospital Universitario
4 Andar, Unidade Pesq TB
Rio de Janeiro
Brazil
Tel: +55-21-25622426
Fax: +55-21-25506903
Email: kritskia@gmail.com
Website:www.ufrj.br
6 Paul D. van Helden Stellenbosch University
Faculty of Health Sciences
Department of Medical Biochemistry
P.O. box 19063
7505 Tygerberg
South Africa
Tel: +27-21-9389124
Fax: +27-21-9389476
E-mail: pvh@sun.ac.za
Website: http://academic.sun.ac.za/med
_biochem/index.html
7 Brigitte Gicquel Institut Pasteur
28, Rue du dr. Roux
75015 Paris
Cedex 15
France
Tel: +33-1-45-688828
Fax: +33-1-45-688843
E-mail: bgicquel@pasteur.fr
Website:http://www.pasteur.fr
8 Abigail Wright World Health Organisation (WHO)
Stop TB department
20 Avenue Appia
1211 Geneva
Switzerland
Tel: +41-22-7914975
E-mail: wrighta@who.int
Website:http://www.who.int
9 Martien.W. Borgdorff KNCV Tuberculosis Foundation
P.O. box 146
2501 CC Den Haag
The Netherlands
Tel: +31-70-416722
Fax: +31-70-3584004
E-mail: borgdorffm@kncvtbc.nl
Website:www.tuberculose.nl
10 T. Trao Vu National Institute of Hygiene
and Epidemiology (NIHE)
1 Yersin street
Hanoi
Viet Nam
Tel: +84-4-9715470
Fax: +84-4-9715470
E-mail: trao@hn.vnn.vn
11 Tone Tønjum Rikshospitalet- Radiumhospitalet
Health Authority
Centre for Molecular Biology
and Neuroscience
Institute of Medical Microbiology
Sognsvannsvn. 20
NO-0027 Oslo
Norway
Tel: +47-23-074065
Fax: +47-23-074061
Email: tone.tonjum@medisin.uio.no
Website:www.cmbn.no

 
 
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