Sebastien Gagneux

MRC National Institute for Medical Research, Londinium, England, United Kingdom

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Publications (20)78.56 Total impact

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    ABSTRACT: Existing small animal models of tuberculosis (TB) rarely develop cavitary disease limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis (Mtb) of varying pathogenic potential. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum (Maf). All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequellae that could be monitored in real time using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, varying extents of extrapulmonary dissemination and varying degrees of cavitation. The majority of live births in this species are twins and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various Mtb strain clades.
    Infection and immunity 05/2013; · 4.21 Impact Factor
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    ABSTRACT: Molecular typing of 964 specimens from patients in Ethiopia with lymph node or pulmonary tuberculosis showed a similar distribution of Mycobacterium tuberculosis strains between the 2 disease manifestations and a minimal role for M. bovis. We report a novel phylogenetic lineage of M. tuberculosis strongly associated with the Horn of Africa
    Emerging Infectious Diseases 04/2013; 19(3). · 6.79 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is a global health problem estimated to kill 1.4 million people per year. Recent advances in the genomics of the causative agents of TB, bacteria known as the Mycobacterium tuberculosis complex (MTBC), have allowed a better comprehension of its population structure and provided the foundation for molecular evolution analyses. These studies are crucial for a better understanding of TB, including the variation of vaccine efficacy and disease outcome, together with the emergence of drug resistance. Starting from the analysis of 73 publicly available genomes from all of the main MTBC lineages, we have screened for evidences of positive selection a set of 576 genes previously associated with drug resistance or encoding membrane proteins. As expected, since antibiotics constitute strong selective pressure, some of the codons identified correspond to the position of confirmed drug-resistance associated substitutions in the genes embB, rpoB and katG. Furthermore, we identified diversifying selection in specific codons of the genes Rv0176 and Rv1872c coding for MCE1 associated transmembrane protein and a putative L-lactate dehydrogenase, respectively. Amino acid sequence analyses showed that in Rv0176, sites undergoing diversifying selection were in a predicted antigen region that varies between 'modern' lineages and 'ancient' MTBC/BCG strains. In Rv1872c, some of the sites under selection are predicted to impact protein function and thus might result from metabolic adaptation. These results illustrate that diversifying selection in MTBC is happening as a consequence of both antibiotic treatment and other evolutionary pressures.
    Molecular Biology and Evolution 02/2013; · 10.35 Impact Factor
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    ABSTRACT: The review attempts to highlight recent advances in understanding the epidemiology, pathogenesis and treatment of tuberculosis. Strategies in the development of new tools should consider the needs of target populations that are dictated by the diversity in host and pathogen genetics.
    African journal of microbiology research 01/2013; 7(2):73-81. · 0.54 Impact Factor
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    ABSTRACT: Current tools available to study the molecular epidemiology of tuberculosis do not provide information about the directionality and sequence of transmission for tuberculosis cases occurring over a short period of time, such as during an outbreak. Recently, whole genome sequencing has been used to study molecular epidemiology of over short time periods. To describe the microevolution of during an outbreak caused by one drug-susceptible strain. METHOD AND MEASUREMENTS: We included 9 patients with tuberculosis diagnosed during a period of 22 months, from a population-based study of the molecular epidemiology in San Francisco. Whole genome sequencing was performed using Illumina's sequencing by synthesis technology. A custom program written in Python was used to determine single nucleotide polymorphisms which were confirmed by PCR product Sanger sequencing. We obtained an average of 95.7% (94.1-96.9%) coverage for each isolate and an average fold read depth of 73 (1 to 250). We found 7 single nucleotide polymorphisms among the 9 isolates. The single nucleotide polymorphisms data confirmed all except one known epidemiological link. The outbreak strain resulted in 5 bacterial variants originating from the index case A1 with 0-2 mutations per transmission event that resulted in a secondary case. Whole genome sequencing analysis from a recent outbreak of tuberculosis enabled us to identify microevolutionary events observable during transmission, to determine 0-2 single nucleotide polymorphisms per transmission event that resulted in a secondary case, and to identify new epidemiologic links in the chain of transmission.
    PLoS ONE 01/2013; 8(3):e58235. · 3.73 Impact Factor
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    ABSTRACT: Rifampicin resistance in clinical isolates of Mycobacterium tuberculosis arises primarily through the selection of bacterial variants harbouring mutations in the 81 base-pair rifampicin resistance determining region of the rpoB gene. Whilst these mutations were shown to infer a fitness-cost in the absence of antibiotic pressure, compensatory mutations in rpoA and rpoC were identified, which restore the fitness of rifampicin-resistant bacteria carrying mutations in rpoB. To investigate the epidemiological relevance of these compensatory mutations, we analysed 286 drug-resistant and 54 drug-susceptible clinical M. tuberculosis isolates from Cape Town, South Africa, a high-incidence setting of multidrug-resistant tuberculosis. Sequencing of a portion of the RpoA-RpoC interaction region of the rpoC gene revealed that 23.5% of all rifampicin-resistant isolates tested carried a non-synonymous mutation in this region. These putative compensatory mutations in rpoC were associated with transmission; as 30.8% of all rifampicin-resistant isolates with an IS6110 RFLP pattern belonging to a recognized RFLP cluster harboured putative rpoC mutations. Such mutations were present in only 9.4% of rifampicin-resistant isolates with unique RFLP patterns (p<0.01). Moreover, these putative compensatory mutations were associated with specific strain genotypes, and the rpoB S531L rifampicin resistance mutation. Among isolates harbouring this rpoB mutation, 44.1% also harboured rpoC mutations while only 4.1% of the isolates with other rpoB mutations exhibited mutations in rpoC (p<0.001). Our study supports a role for rpoC mutations in the transmission of MDR-TB, and illustrates how epistatic interactions between drug resistance-conferring mutations, compensatory mutations, and different strain genetic backgrounds might influence compensatory evolution in drug-resistant M. tuberculosis.
    Antimicrobial Agents and Chemotherapy 12/2012; · 4.57 Impact Factor
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    ABSTRACT: Monitoring drug resistance in Mycobacterium tuberculosis is essential to curb the spread of tuberculosis (TB). Unfortunately, drug susceptibility testing is currently not available in Papua New Guinea (PNG) and that impairs TB control in this country. We report for the first time M. tuberculosis mutations associated with resistance to first and second-line anti-TB drugs in Madang, PNG. A molecular cluster analysis was performed to identify M. tuberculosis transmission in that region. Phenotypic drug susceptibility tests showed 15.7% resistance to at least one drug and 5.2% multidrug resistant (MDR) TB. Rifampicin resistant strains had the rpoB mutations D516F, D516Y or S531L; Isoniazid resistant strains had the mutations katG S315T or inhA promoter C15T; Streptomycin resistant strains had the mutations rpsL K43R, K88Q, K88R), rrs A514C or gidB V77G. The molecular cluster analysis indicated evidence for transmission of resistant strain. We observed a substantial rate of MDR-TB in the Madang area of PNG associated with mutations in specific genes. A close monitoring of drug resistance is therefore urgently required, particularly in the presence of drug-resistant M. tuberculosis transmission. In the absence of phenotypic drug susceptibility testing in PNG, molecular assays for drug resistance monitoring would be of advantage.
    BMC Microbiology 09/2012; 12:191. · 3.10 Impact Factor
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    ABSTRACT: The Beijing family of Mycobacterium tuberculosis strains is part of lineage 2 (also known as the East Asian lineage). In clinical studies, we have observed that isolates from the sublineage RD207 of lineage 2 were more readily transmitted among humans. To investigate the basis for this difference, we tested representative strains with the characteristic Beijing spoligotype from four of the five sublineages of lineage 2 in the guinea pig model and subjected these strains to comparative whole-genome sequencing. The results of these studies showed that all of the clinical strains were capable of growing and causing lung pathology in guinea pigs after low-dose aerosol exposure. Differences between the abilities of the four sublineages to grow in the lungs of these animals were not overt, but members of RD207 were significantly more pathogenic, resulting in severe lung damage. The RD207 strains also induced much higher levels of markers associated with regulatory T cells and showed a significant loss of activated T cells in the lungs over the course of the infections. Whole-genome sequencing of the strains revealed mutations specific for RD207 which may explain this difference. Based on these data, we hypothesize that the sublineages of M. tuberculosis are associated with distinct pathological and clinical phenotypes and that these differences influence the transmissibility of particular M. tuberculosis strains in human populations.
    Clinical and vaccine Immunology: CVI 06/2012; 19(8):1227-37. · 2.60 Impact Factor
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    ABSTRACT: Madang and surroundings, Papua New Guinea (PNG). To characterise the genetic diversity and drug susceptibility of Mycobacterium tuberculosis isolates collected in Madang and surroundings. M. tuberculosis was isolated from sputum samples from active pulmonary tuberculosis cases. Drug resistance profiles were obtained by drug susceptibility testing. M. tuberculosis lineages were identified by single nucleotide polymorphisms and sub-typing was performed by spoligotyping. Spoligotyping and 24 locus mycobacterial interspersed repetitive units-variable number of tandem repeats were combined to identify clustered isolates. The 173 M. tuberculosis isolates collected belonged predominantly to the Euro-American lineage (Lineage 4) and the East-Asian lineage (Lineage 2). Multidrug-resistant M. tuberculosis were observed in 5.2% of isolates. Lineage 2 M. tuberculosis, which includes the 'Beijing' genotype, was significantly associated with any drug resistance (OR 5.2, 95%CI 1.8-15.1). Cluster analyses showed 44% molecularly clustered isolates, suggesting transmission of M. tuberculosis in the community, including transmission of primary drug-resistant M. tuberculosis. These data provide the first insight into the molecular characteristics of M. tuberculosis in the Madang area of PNG, and indicate substantial drug resistance with evidence of ongoing transmission.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 06/2012; 16(8):1100-7. · 2.61 Impact Factor
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    Sebastien Gagneux
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    ABSTRACT: Tuberculosis (TB) is a disease of antiquity. Yet TB today still causes more adult deaths than any other single infectious disease. Recent studies show that contrary to the common view postulating an animal origin for TB, Mycobacterium tuberculosis complex (MTBC), the causative agent of TB, emerged as a human pathogen in Africa and colonized the world accompanying the Out-of-Africa migrations of modern humans. More recently, evolutionarily 'modern' lineages of MTBC expanded as a consequence of the global human population increase, and spread throughout the world following waves of exploration, trade and conquest. While epidemiological data suggest that the different phylogenetic lineages of MTBC might have adapted to different human populations, overall, the phylogenetically 'modern' MTBC lineages are more successful in terms of their geographical spread compared with the 'ancient' lineages. Interestingly, the global success of 'modern' MTBC correlates with a hypo-inflammatory phenotype in macrophages, possibly reflecting higher virulence, and a shorter latency in humans. Finally, various human genetic variants have been associated with different MTBC lineages, suggesting an interaction between human genetic diversity and MTBC variation. In summary, the biology and the epidemiology of human TB have been shaped by the long-standing association between MTBC and its human host.
    Philosophical Transactions of The Royal Society B Biological Sciences 03/2012; 367(1590):850-9. · 6.23 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis, the causative agent of most human tuberculosis, infects one third of the world's population and kills an estimated 1.7 million people a year. With the world-wide emergence of drug resistance, and the finding of more functional genetic diversity than previously expected, there is a renewed interest in understanding the forces driving genome evolution of this important pathogen. Genetic diversity in M. tuberculosis is dominated by single nucleotide polymorphisms and small scale gene deletion, with little or no evidence for large scale genome rearrangements seen in other bacteria. Recently, a single report described a large scale genome duplication that was suggested to be specific to the Beijing lineage. We report here multiple independent large-scale duplications of the same genomic region of M. tuberculosis detected through whole-genome sequencing. The duplications occur in strains belonging to both M. tuberculosis lineage 2 and 4, and are thus not limited to Beijing strains. The duplications occur in both drug-resistant and drug susceptible strains. The duplicated regions also have substantially different boundaries in different strains, indicating different originating duplication events. We further identify a smaller segmental duplication of a different genomic region of a lab strain of H37Rv. The presence of multiple independent duplications of the same genomic region suggests either instability in this region, a selective advantage conferred by the duplication, or both. The identified duplications suggest that large-scale gene duplication may be more common in M. tuberculosis than previously considered.
    PLoS ONE 01/2012; 7(2):e26038. · 3.73 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of "classical" antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design.
    PLoS ONE 01/2012; 7(4):e30593. · 3.73 Impact Factor
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    Daniela Brites, Sebastien Gagneux
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    ABSTRACT: Tuberculosis (TB) has been affecting humans for millennia. There is increasing indication that human-adapted Mycobacterium tuberculosis complex (MTBC) has been co-evolving with different human populations. Some of the most important drivers of MTBC evolution have been the host immune response and human demography. These old selective forces have shaped many of the features of human TB we see today. Two new selective pressures have emerged only a few decades ago, namely HIV co-infection and the use of anti-TB drugs. Here we discuss how the emergence of HIV/TB and drug resistance could impact the long-term balance between MTBC and its human host, and how these changes might influence the future evolutionary trajectory of MTBC.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 08/2011; 12(4):678-85. · 3.22 Impact Factor
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    S Borrell, S Gagneux
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    ABSTRACT: Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in this organism has been underestimated. We review our current understanding of the genetic diversity among M. tuberculosis clinical strains and discuss the relevance of this diversity for the ongoing global epidemics of drug-resistant tuberculosis. Based on findings in other bacteria, we propose that epistatic interactions between pre-existing differences in strain genetic background, acquired drug-resistance-conferring mutations and compensatory changes could play a role in the emergence and spread of drug-resistant M. tuberculosis.
    Clinical Microbiology and Infection 06/2011; 17(6):815-20. · 4.58 Impact Factor
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    ABSTRACT: The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed for different pro-inflammatory cytokines and chemokines, and was conserved across multiple human donors. Although each major phylogenetic lineage of MTBC included strains inducing a range of cytokine responses, we found that overall inflammatory phenotypes differed significantly across lineages. In particular, comparison of evolutionarily modern lineages demonstrated a significant skewing towards lower early inflammatory response. The differential response to ancient and modern lineages observed using GM-CSF derived macrophages was also observed in autologous monocyte-derived dendritic cells and murine bone marrow-derived macrophages, but not in human unfractionated peripheral blood mononuclear cells. We hypothesize that the reduced immune responses to modern lineages contribute to more rapid disease progression and transmission, which might be a selective advantage in the context of expanding human populations. In addition to the lineage effects, the large strain-to-strain variation in innate immune responses elicited by MTBC will need to be considered in tuberculosis vaccine development.
    PLoS Pathogens 03/2011; 7(3):e1001307. · 8.14 Impact Factor
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    ABSTRACT: Spoligotyping is used in molecular epidemiological studies, and signature patterns have identified strain families. However, homoplasy occurs in the markers used for spoligotyping, which could lead to identical spoligotypes in phylogenetically unrelated strains. We determined the accuracy of strain classification based on spoligotyping using the six large sequence and single nucleotide polymorphisms-defined lineages as a gold standard. Of 919 Mycobacterium tuberculosis isolates, 870 (95%) were classified into a spoligotype family. Strains from a particular spoligotype family belonged to the same lineage. We did not find convergence to the same spoligotype. Spoligotype families appear to be sub-lineages within the main lineages.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 01/2011; 15(1):131-3. · 2.61 Impact Factor
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    ABSTRACT: Spoligotyping is used in molecular epidemiological studies, and signature patterns have identified strain families. However, homoplasy occurs in the markers used for spoligotyping, which could lead to identical spoligotypes in phylogenetically unrelated strains. We determined the accuracy of strain classification based on spoligotyping using the six large sequence and single nucleotide polymorphisms-defined lineages as a gold standard. Of 919 Mycobacterium tuberculosis isolates, 870 (95%) were classified into a spoligotype family. Strains from a particular spoligotype family belonged to the same lineage. We did not find convergence to the same spoligotype. Spoligotype families appear to be sub-lineages within the main lineages.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 12/2010; 15(1):131-133. · 2.61 Impact Factor
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    Mireilla Coscolla, Sebastien Gagneux
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    ABSTRACT: The outcome of tuberculosis infection and disease is highly variable. This variation has been attributed primarily to host and environmental factors, but better understanding of the global genomic diversity in the M. tuberculosis complex (MTBC) suggests that bacterial factors could also be involved. Review of nearly 100 published reports shows that MTBC strains differ in their virulence and immunogenicity in experimental models, but whether this phenotypic variation plays a role in human disease remains unclear. Given the complex interactions between the host, the pathogen and the environment, linking MTBC genotypic diversity to experimental and clinical phenotypes requires an integrated systems epidemiology approach embedded in a robust evolutionary framework.
    Drug Discovery Today Disease Mechanisms 01/2010; 7(1):e43-e59.
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    S Borrell, S Gagneux
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    ABSTRACT: Mathematical models predict that the future of the multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemic will depend to a large extent on the transmission efficiency or relative fitness of drug-resistant Mycobacterium tuberculosis compared to drug-susceptible strains. Molecular epidemiological studies comparing the spread of drug-resistant to that of drug-susceptible strains have yielded conflicting results: MDR strains can be up to 10 times more or 10 times less transmissible than pan-susceptible strains. Experimental work performed with model organisms has highlighted a level of complexity in the biology of bacterial drug resistance that is generally not considered during standard epidemiological studies of TB transmission. Recent experimental studies in M. tuberculosis indicate that drug resistance in this organism could be equally complex. For example, the relative fitness of drug-resistant strains of M. tuberculosis can be influenced by the specific drug resistance-conferring mutation and strain genetic background. Furthermore, compensatory evolution, which has been shown to mitigate the fitness defects associated with drug resistance in other bacteria, could be an important factor in the emergence and spread of drug-resistant M. tuberculosis. However, much more work is needed to understand the detailed molecular mechanisms and evolutionary forces that drive drug resistance in this pathogen. Such increased knowledge will allow for better epidemiological predictions and assist in the development of new tools and strategies to fight drug-resistant TB.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 12/2009; 13(12):1456-66. · 2.61 Impact Factor
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    S. Borrell, S. Gagneux
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    ABSTRACT: Mathematical models predict that the future of the multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemic will depend to a large extent on the transmission efficiency or relative fitness of drug-resistant Mycobacterium tuberculosis compared to drug-susceptible strains. Molecular epidemiological studies comparing the spread of drug-resistant to that of drug-susceptible strains have yielded conflicting results: MDR strains can be up to 10 times more or 10 times less transmissible than pan-susceptible strains. Experimental work performed with model organisms has highlighted a level of complexity in the biology of bacterial drug resistance that is generally not considered during standard epidemiological studies of TB transmission. Recent experimental studies in M. tuberculosis indicate that drug resistance in this organism could be equally complex. For example, the relative fitness of drug-resistant strains of M. tuberculosis can be influenced by the specific drug resistance-conferring mutation and strain genetic background. Furthermore, compensatory evolution, which has been shown to mitigate the fitness defects associated with drug resistance in other bacteria, could be an important factor in the emergence and spread of drug-resistant M. tuberculosis. However, much more work is needed to understand the detailed molecular mechanisms and evolutionary forces that drive drug resistance in this pathogen. Such increased knowledge will allow for better epidemiological predictions and assist in the development of new tools and strategies to fight drug-resistant TB.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 11/2009; 13(12):1456-1466. · 2.61 Impact Factor

Publication Stats

248 Citations
78.56 Total Impact Points

Institutions

  • 2012
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom
  • 2010–2012
    • Swiss Tropical and Public Health Institute
      Bâle, Basel-City, Switzerland
  • 2011
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 2009
    • Medical Research Council (UK)
      Londinium, England, United Kingdom