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Integrating Genomic and Ecologic Approaches to Understand the Nature and Consequence of Genetic Diversity in Mycobacterium tuberculosis

English title Integrating Genomic and Ecologic Approaches to Understand the Nature and Consequence of Genetic Diversity in Mycobacterium tuberculosis
Applicant Gagneux Sebastien
Number 119205
Funding scheme SNSF Professorships
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Experimental Microbiology
Start/End 01.03.2010 - 28.02.2014
Approved amount 1'590'034.00
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All Disciplines (6)

Discipline
Experimental Microbiology
Molecular Biology
Immunology, Immunopathology
Infectious Diseases
Medical Microbiology
Ecology

Keywords (22)

drug resistance; population genetics; coevolution; molecular epidemiology; fitness; virulence; mycobacteria; gene expression; Tuberculosis; evolution; compensation; biogeography; phylogenetics; population genomics; epidemiology; microbiology; genomics; population; genotyping; bacteria; antibiotic; DNA

Lay Summary (English)

Lead
Lay summary
Tuberculosis remains a global public health emergency killing someone every 15 seconds. There is an urgent need to improve our understanding of the evolution of the causative agent of tuberculosis, Mycobacterium tuberculosis, as new strains of this bacterium are emerging which are resistant to most available drugs. Furthermore, different genetic variants of M. tuberculosis circulate in different parts of the world. However, whether genetic diversity in M. tuberculosis will affect the effectiveness of new tuberculosis vaccines and other control measures currently in development is unclear.Goals and Research Questions:The overall goal of this project is to study the genetic diversity and evolution of M. tuberculosis and their impact on the clinical manifestation of tuberculosis and its control. We are addressing the following four research questions: 1) What are the effects of drug resistance on the virulence of M. tuberculosis? 2) How do drug-resistant strains of M. tuberculosis evolve as a consequence of these effects? 3) What are the genetic differences between the main global variants of M. tuberculosis? 4) How does the human host perceive these different variants?Approach: We collaborate with a number of international research groups across the world, including regions in Africa and Asia where tuberculosis is highly endemic. Through these links, we get access to relevant clinical strains of M. tuberculosis from a variety of geographical settings. We use a series of high-throughput genomic analyses tools to study the genetic diversity among these bacterial strains. In addition, we perform targeted experimental studies with live M. tuberculosis to investigate aspects of the host-pathogen interaction. These genomic and experimental data are then integrated with detailed epidemiological information from various clinical settings.Expected Outcomes: Our work will help improve our understanding of the causes and consequences of genetic diversity in M. tuberculosis. This knowledge will be able to inform the development and deployment of better tools and strategies to control tuberculosis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Evaluation of Customised Lineage-Specific Sets of MIRU-VNTR Loci for Genotyping Mycobacterium tuberculosis Complex Isolates in Ghana.
Asante-Poku Adwoa, Nyaho Michael Selasi, Borrell Sonia, Comas Iñaki, Gagneux Sebastien, Yeboah-Manu Dorothy (2014), Evaluation of Customised Lineage-Specific Sets of MIRU-VNTR Loci for Genotyping Mycobacterium tuberculosis Complex Isolates in Ghana., in PloS one, 9(3), 92675-92675.
Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition.
Copin Richard, Coscollá Mireia, Seiffert Salome N, Bothamley Graham, Sutherland Jayne, Mbayo Georgetta, Gagneux Sebastien, Ernst Joel D (2014), Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition., in mBio, 5(1), 00960-13.
Advances in tuberculosis
Aseffa A, Mihret A, Habte A, Abebe M, Wassie L, Tschopp R, Beyene D, Ameni G, Berg S, Doherty TM, Gagneux S, Young D, Howe R (2013), Advances in tuberculosis, in Afri J Microbio Res , 7, 73.
Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus).
Via Laura E, Weiner Danielle M, Schimel Daniel, Lin Philana Ling, Dayao Emmanuel, Tankersley Sarah L, Cai Ying, Coleman M Teresa, Tomko Jaime, Paripati Praveen, Orandle Marlene, Kastenmayer Robin J, Tartakovsky Michael, Rosenthal Alexander, Portevin Damien, Eum Seok Yong, Lahouar Saher, Gagneux Sebastien, Young Douglas B, Flynn Joanne L, Barry Clifton E (2013), Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)., in Infection and immunity, 81(8), 2909-19.
Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis.
Borrell Sònia, Teo Youjin, Giardina Federica, Streicher Elizabeth M, Klopper Marisa, Feldmann Julia, Müller Borna, Victor Tommie C, Gagneux Sebastien (2013), Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis., in Evolution, medicine, and public health, 2013(1), 65-74.
Evidence for Diversifying Selection in a Set of Mycobacterium tuberculosis Genes in Response to Antibiotic- and Nonantibiotic-Related Pressure.
Osório Nuno S, Rodrigues Fernando, Gagneux Sebastien, Pedrosa Jorge, Pinto-Carbó Marta, Castro António G, Young Douglas, Comas Iñaki, Saraiva Margarida (2013), Evidence for Diversifying Selection in a Set of Mycobacterium tuberculosis Genes in Response to Antibiotic- and Nonantibiotic-Related Pressure., in Molecular biology and evolution, 30(6), 1326-36.
Genetic diversity in Mycobacterium tuberculosis
Gagneux Sebastien (2013), Genetic diversity in Mycobacterium tuberculosis, in McKinney John, Pieters Jean (ed.), Springer-Verlag, Heidelberg, 1.
Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis.
Farhat Maha R, Shapiro B Jesse, Kieser Karen J, Sultana Razvan, Jacobson Karen R, Victor Thomas C, Warren Robin M, Streicher Elizabeth M, Calver Alistair, Sloutsky Alex, Kaur Devinder, Posey Jamie E, Plikaytis Bonnie, Oggioni Marco R, Gardy Jennifer L, Johnston James C, Rodrigues Mabel, Tang Patrick K C, Kato-Maeda Midori, Borowsky Mark L, Muddukrishna Bhavana, Kreiswirth Barry N, Kurepina Natalia, Galagan James, Gagneux Sebastien (2013), Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis., in Nature genetics, 45(10), 1183-9.
HIV Infection Disrupts the Sympatric Host-Pathogen Relationship in Human Tuberculosis.
Fenner Lukas, Egger Matthias, Bodmer Thomas, Furrer Hansjakob, Ballif Marie, Battegay Manuel, Helbling Peter, Fehr Jan, Gsponer Thomas, Rieder Hans L, Zwahlen Marcel, Hoffmann Matthias, Bernasconi Enos, Cavassini Matthias, Calmy Alexandra, Dolina Marisa, Frei Reno, Janssens Jean-Paul, Borrell Sonia, Stucki David, Schrenzel Jacques, Böttger Erik C, Gagneux Sebastien, Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups (2013), HIV Infection Disrupts the Sympatric Host-Pathogen Relationship in Human Tuberculosis., in PLoS genetics, 9(3), 1003318-1003318.
Interaction between the genetic diversity of M. tuberculosis and the genetic variability of humans and its relevance for tuberculosis vaccines
Gagneux Sebastien (2013), Interaction between the genetic diversity of M. tuberculosis and the genetic variability of humans and its relevance for tuberculosis vaccines, in Mohd Nor Norazmi, Acosta Armando, Sarmiento Maria Elena (ed.), Oxford University Press, Shah Alam, 337.
Long-term dominance of Mycobacterium tuberculosis Uganda family in peri-urban Kampala-Uganda is not associated with cavitary disease.
Wampande Eddie M, Mupere Ezekiel, Debanne Sara M, Asiimwe Benon B, Nsereko Mary, Mayanja Harriet, Eisenach Kathleen, Kaplan Gilla, Boom Henry W, Gagneux Sebastien, Joloba Moses L (2013), Long-term dominance of Mycobacterium tuberculosis Uganda family in peri-urban Kampala-Uganda is not associated with cavitary disease., in BMC infectious diseases, 13, 484-484.
Mapping of genotype-phenotype diversity among clinical isolates of mycobacterium tuberculosis by sequence-based transcriptional profiling.
Rose Graham, Cortes Teresa, Comas Iñaki, Coscolla Mireia, Gagneux Sebastien, Young Douglas B (2013), Mapping of genotype-phenotype diversity among clinical isolates of mycobacterium tuberculosis by sequence-based transcriptional profiling., in Genome biology and evolution, 5(10), 1849-62.
Mycobacterial lineages causing pulmonary and extrapulmonary tuberculosis, ethiopia.
Firdessa Rebuma, Berg Stefan, Hailu Elena, Schelling Esther, Gumi Balako, Erenso Girume, Gadisa Endalamaw, Kiros Teklu, Habtamu Meseret, Hussein Jemal, Zinsstag Jakob, Robertson Brian D, Ameni Gobena, Lohan Amanda J, Loftus Brendan, Comas Iñaki, Gagneux Sebastien, Tschopp Rea, Yamuah Lawrence, Hewinson Glyn, Gordon Stephen V, Young Douglas B, Aseffa Abraham (2013), Mycobacterial lineages causing pulmonary and extrapulmonary tuberculosis, ethiopia., in Emerging infectious diseases, 19(3), 460-3.
Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis.
Ford Christopher B, Shah Rupal R, Maeda Midori Kato, Gagneux Sebastien, Murray Megan B, Cohen Ted, Johnston James C, Gardy Jennifer, Lipsitch Marc, Fortune Sarah M (2013), Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis., in Nature genetics, 45(7), 784-90.
Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee
Coscolla M, Lewin A, Metzger S, Maetz-Rennsing K, Calvignac-Spencer S, Nitsche A, Dabrowski PW, Radonic A, Niemann S, Parkhill J, Couacy-Hymann E, Feldman J, Comas I, Boesch C, Gagneux S, Leendertz FH (2013), Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee, in Emerging Infectious Diseases, 19(6), 969-976.
Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans.
Comas Iñaki, Coscolla Mireia, Luo Tao, Borrell Sonia, Holt Kathryn E, Kato-Maeda Midori, Parkhill Julian, Malla Bijaya, Berg Stefan, Thwaites Guy, Yeboah-Manu Dorothy, Bothamley Graham, Mei Jian, Wei Lanhai, Bentley Stephen, Harris Simon R, Niemann Stefan, Diel Roland, Aseffa Abraham, Gao Qian, Young Douglas, Gagneux Sebastien (2013), Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans., in Nature genetics, 45(10), 1176-82.
Programmatically selected multidrug-resistant strains drive the emergence of extensively drug-resistant tuberculosis in South Africa.
Müller Borna, Chihota Violet N, Pillay Manormoney, Klopper Marisa, Streicher Elizabeth M, Coetzee Gerrit, Trollip Andre, Hayes Cindy, Bosman Marlein E, Gey van Pittius Nicolaas C, Victor Thomas C, Gagneux Sebastien, van Helden Paul D, Warren Robin M (2013), Programmatically selected multidrug-resistant strains drive the emergence of extensively drug-resistant tuberculosis in South Africa., in PloS one, 8(8), 70919-70919.
Putative Compensatory Mutations in the rpoC Gene of Rifampin-Resistant Mycobacterium tuberculosis Are Associated with Ongoing Transmission.
de Vos M, Müller B, Borrell S, Black P A, van Helden P D, Warren R M, Gagneux S, Victor T C (2013), Putative Compensatory Mutations in the rpoC Gene of Rifampin-Resistant Mycobacterium tuberculosis Are Associated with Ongoing Transmission., in Antimicrobial agents and chemotherapy, 57(2), 827-32.
Single nucleotide polymorphisms in Mycobacterium tuberculosis and the need for a curated database.
Stucki David, Gagneux Sebastien (2013), Single nucleotide polymorphisms in Mycobacterium tuberculosis and the need for a curated database., in Tuberculosis (Edinburgh, Scotland), 93(1), 30-9.
The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis.
Müller Borna, Borrell Sonia, Rose Graham, Gagneux Sebastien (2013), The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis., in Trends in genetics : TIG, 29(3), 160-9.
Use of Whole Genome Sequencing to Determine the Microevolution of Mycobacterium tuberculosis during an Outbreak.
Kato-Maeda Midori, Ho Christine, Passarelli Ben, Banaei Niaz, Grinsdale Jennifer, Flores Laura, Anderson Jillian, Murray Megan, Rose Graham, Kawamura L Masae, Pourmand Nader, Tariq Muhammad A, Gagneux Sebastien, Hopewell Philip C (2013), Use of Whole Genome Sequencing to Determine the Microevolution of Mycobacterium tuberculosis during an Outbreak., in PloS one, 8(3), 58235-58235.
A case of cutaneous tuberculosis in a buruli ulcer-endemic area.
Bratschi Martin W, Njih Tabah Earnest, Bolz Miriam, Stucki David, Borrell Sonia, Gagneux Sebastien, Noumen-Djeunga Blanbin, Junghanss Thomas, Um Boock Alphonse, Pluschke Gerd (2012), A case of cutaneous tuberculosis in a buruli ulcer-endemic area., in PLoS neglected tropical diseases, 6(8), 1751-1751.
Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig.
Kato-Maeda Midori, Shanley Crystal A, Ackart David, Jarlsberg Leah G, Shang Shaobin, Obregon-Henao Andres, Harton Marisabel, Basaraba Randall J, Henao-Tamayo Marcela, Barrozo Joyce C, Rose Jordan, Kawamura L Masae, Coscolla Mireia, Fofanov Viacheslav Y, Koshinsky Heather, Gagneux Sebastien, Hopewell Philip C, Ordway Diane J, Orme Ian M (2012), Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig., in Clinical and vaccine immunology : CVI, 19(8), 1227-37.
Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints.
McEvoy Christopher R E, Cloete Ruben, Müller Borna, Schürch Anita C, van Helden Paul D, Gagneux Sebastien, Warren Robin M, Gey van Pittius Nicolaas C (2012), Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints., in PloS one, 7(3), 30593-30593.
Drug resistance-conferring mutations in Mycobacterium tuberculosis from Madang, Papua New Guinea.
Ballif Marie, Harino Paul, Ley Serej, Coscolla Mireia, Niemann Stefan, Carter Robyn, Coulter Christopher, Borrell Sonia, Siba Peter, Phuanukoonnon Suparat, Gagneux Sebastien, Beck Hans-Peter (2012), Drug resistance-conferring mutations in Mycobacterium tuberculosis from Madang, Papua New Guinea., in BMC microbiology, 12(1), 191-191.
Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.
Fenner Lukas, Egger Matthias, Bodmer Thomas, Altpeter Ekkehardt, Zwahlen Marcel, Jaton Katia, Pfyffer Gaby E, Borrell Sonia, Dubuis Olivier, Bruderer Thomas, Siegrist Hans H, Furrer Hansjakob, Calmy Alexandra, Fehr Jan, Stalder Jesica Mazza, Ninet Béatrice, Böttger Erik C, Gagneux Sebastien, Swiss HIV Cohort Study and the Swiss Molecular Epidemiology of Tuberculosis Study Group (2012), Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis., in Antimicrobial agents and chemotherapy, 56(6), 3047-53.
First Insights into the Phylogenetic Diversity of Mycobacterium tuberculosis in Nepal.
Malla Bijaya, Stucki David, Borrell Sonia, Feldmann Julia, Maharjan Bhagwan, Shrestha Bhawana, Fenner Lukas, Gagneux Sebastien (2012), First Insights into the Phylogenetic Diversity of Mycobacterium tuberculosis in Nepal., in PloS one, 7(12), 52297-52297.
Genetic diversity of Mycobacterium tuberculosis in Madang, Papua New Guinea.
Ballif M, Harino P, Ley S, Carter R, Coulter C, Niemann S, Borrell S, Fenner L, Siba P, Phuanukoonnon S, Gagneux S, Beck H-P (2012), Genetic diversity of Mycobacterium tuberculosis in Madang, Papua New Guinea., in The international journal of tuberculosis and lung disease : the official journal of the Internation, 16(8), 1100-7.
Host-pathogen coevolution in human tuberculosis.
Gagneux Sebastien (2012), Host-pathogen coevolution in human tuberculosis., in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1590), 850-9.
Independent Large Scale Duplications in Multiple M. tuberculosis Lineages Overlapping the Same Genomic Region.
Weiner Brian, Gomez James, Victor Thomas C, Warren Robert M, Sloutsky Alexander, Plikaytis Bonnie B, Posey James E, van Helden Paul D, Gey van Pittius Nicolass C, Koehrsen Michael, Sisk Peter, Stolte Christian, White Jared, Gagneux Sebastien, Birren Bruce, Hung Deborah, Murray Megan, Galagan James (2012), Independent Large Scale Duplications in Multiple M. tuberculosis Lineages Overlapping the Same Genomic Region., in PloS one, 7(2), 26038-26038.
Mycobacterium tuberculosis Transmission in a Country with Low Tuberculosis Incidence: Role of Immigration and HIV Infection.
Fenner Lukas, Gagneux Sebastien, Helbling Peter, Battegay Manuel, Rieder Hans L, Pfyffer Gaby E, Zwahlen Marcel, Furrer Hansjakob, Siegrist Hans H, Fehr Jan, Dolina Marisa, Calmy Alexandra, Stucki David, Jaton Katia, Janssens Jean-Paul, Stalder Jesica Mazza, Bodmer Thomas, Ninet Beatrice, Böttger Erik C, Egger Matthias, for the Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups (2012), Mycobacterium tuberculosis Transmission in a Country with Low Tuberculosis Incidence: Role of Immigration and HIV Infection., in Journal of clinical microbiology, 50(2), 388-395.
Old and new selective pressures on Mycobacterium tuberculosis.
Brites Daniela, Gagneux Sebastien (2012), Old and new selective pressures on Mycobacterium tuberculosis., in Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in i, 12(4), 678-85.
The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex.
Bentley Stephen D, Comas Iñaki, Bryant Josephine M, Walker Danielle, Smith Noel H, Harris Simon R, Thurston Scott, Gagneux Sebastien, Wood Jonathan, Antonio Martin, Quail Michael A, Gehre Florian, Adegbola Richard A, Parkhill Julian, de Jong Bouke C (2012), The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex., in PLoS neglected tropical diseases, 6(2), 1552-1552.
Tuberculosis in HIV-Negative and HIV-Infected Patients in a Low-Incidence Country: Clinical Characteristics and Treatment Outcomes.
Fenner Lukas, Gagneux Sebastien, Janssens Jean-Paul, Fehr Jan, Cavassini Matthias, Hoffmann Matthias, Bernasconi Enos, Schrenzel Jacques, Bodmer Thomas, Böttger Erik C, Helbling Peter, Egger Matthias, for the Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups (2012), Tuberculosis in HIV-Negative and HIV-Infected Patients in a Low-Incidence Country: Clinical Characteristics and Treatment Outcomes., in PloS one, 7(3), 34186-34186.
Two New Rapid SNP-Typing Methods for Classifying Mycobacterium tuberculosis Complex into the Main Phylogenetic Lineages.
Stucki David, Malla Bijaya, Hostettler Simon, Huna Thembela, Feldmann Julia, Yeboah-Manu Dorothy, Borrell Sonia, Fenner Lukas, Comas Iñaki, Coscollà Mireia, Gagneux Sebastien (2012), Two New Rapid SNP-Typing Methods for Classifying Mycobacterium tuberculosis Complex into the Main Phylogenetic Lineages., in PloS one, 7(7), 41253-41253.
Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes.
Comas Iñaki, Borrell Sonia, Roetzer Andreas, Rose Graham, Malla Bijaya, Kato-Maeda Midori, Galagan James, Niemann Stefan, Gagneux Sebastien (2012), Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes., in Nature genetics, 44(1), 106-10.
"Pseudo-Beijing": evidence for convergent evolution in the direct repeat region of Mycobacterium tuberculosis.
Fenner Lukas, Malla Bijaya, Ninet Béatrice, Dubuis Olivier, Stucki David, Borrell Sonia, Huna Thembela, Bodmer Thomas, Egger Matthias, Gagneux Sebastien (2011), "Pseudo-Beijing": evidence for convergent evolution in the direct repeat region of Mycobacterium tuberculosis., in PloS one, 6(9), 24737-24737.
A role for systems epidemiology in tuberculosis research.
Comas Iñaki, Gagneux Sebastien (2011), A role for systems epidemiology in tuberculosis research., in Trends in microbiology, 19(10), 492-500.
Estimating the mutation rate of Mycobacterium tuberculosis during infection.
Sherman David R, Gagneux Sebastien (2011), Estimating the mutation rate of Mycobacterium tuberculosis during infection., in Nature genetics, 43(5), 400-1.
First insight into Mycobacterium tuberculosis genetic diversity and drug resistance conferring mutations in the Democratic Republic of the Congo
Fenner L, Gagneux S, Kabuya G, Stucki D, Kabuyai JP, Borrell S, Frei R, Burri C, Kalemwa D, Egger M, Okiata JP (2011), First insight into Mycobacterium tuberculosis genetic diversity and drug resistance conferring mutations in the Democratic Republic of the Congo, in East African Med J , 88, 409.
Genotypic diversity and drug susceptibility patterns among M. tuberculosis complex isolates from South-Western Ghana.
Yeboah-Manu Dorothy, Asante-Poku Adwoa, Bodmer Thomas, Stucki David, Koram Kwadwo, Bonsu Frank, Pluschke Gerd, Gagneux Sebastien (2011), Genotypic diversity and drug susceptibility patterns among M. tuberculosis complex isolates from South-Western Ghana., in PloS one, 6(7), 21906-21906.
Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.
Portevin Damien, Gagneux Sébastien, Comas Iñaki, Young Douglas (2011), Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages., in PLoS pathogens, 7(3), 1001307-1001307.
Strain classification of Mycobacterium tuberculosis: congruence between large sequence polymorphisms and spoligotypes.
Kato-Maeda M, Gagneux S, Flores L L, Kim E Y, Small P M, Desmond E P, Hopewell P C (2011), Strain classification of Mycobacterium tuberculosis: congruence between large sequence polymorphisms and spoligotypes., in The international journal of tuberculosis and lung disease : the official journal of the Internation, 15(1), 131-3.
Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis.
Borrell S, Gagneux S (2011), Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis., in Clinical microbiology and infection : the official publication of the European Society of Clinical M, 17(6), 815-20.
The rise and fall of Mycobacterium tuberculosis complex
Behr Marcel, Gagneux Sebastien (2011), The rise and fall of Mycobacterium tuberculosis complex, in Tibayrenc Michel (ed.), Elsevier, Burlington, 651-667.
Does M. tuberculosis genomic diversity explain disease diversity?
Coscolla Mireilla, Gagneux Sebastien (2010), Does M. tuberculosis genomic diversity explain disease diversity?, in Drug discovery today. Disease mechanisms, 7(1), 43-59.
Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.
Comas Iñaki, Chakravartti Jaidip, Small Peter M, Galagan James, Niemann Stefan, Kremer Kristin, Ernst Joel D, Gagneux Sebastien (2010), Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved., in Nature genetics, 42(6), 498-503.
Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis.
Nahid Payam, Bliven Erin E, Kim Elizabeth Y, Mac Kenzie William R, Stout Jason E, Diem Lois, Johnson John L, Gagneux Sebastien, Hopewell Philip C, Kato-Maeda Midori, Tuberculosis Trials Consortium (2010), Influence of M. tuberculosis lineage variability within a clinical trial for pulmonary tuberculosis., in PloS one, 5(5), 10753-10753.
Mycobacterium africanum--review of an important cause of human tuberculosis in West Africa.
de Jong Bouke C, Antonio Martin, Gagneux Sebastien (2010), Mycobacterium africanum--review of an important cause of human tuberculosis in West Africa., in PLoS neglected tropical diseases, 4(9), 744-744.
Strain and antigen variation in Mycobacterium tuberculosis: implications for the development of new tools for tuberculosis
Gagneux Sebastien, Brennan Michael (2010), Strain and antigen variation in Mycobacterium tuberculosis: implications for the development of new tools for tuberculosis, in Acosta Armando, Sarmiento Maria Elena, Mohd Nor Norazmi (ed.), Oxford University Press, Shah Alam, 129-146.
Combination of Single Nucleotide Polymorphism and Variable Number Tandem Repeats for genotyping homogenous population of Mycobacterium tuberculosis Beijing strains in China.
Luo Tao, Yang Chongguang, Gagneux Sebastien, Gicquel Brigitte, Jian Mei, Gao Qian, Combination of Single Nucleotide Polymorphism and Variable Number Tandem Repeats for genotyping homogenous population of Mycobacterium tuberculosis Beijing strains in China., in Journal of clinical microbiology.
Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
Borrell S, Teo Y, Giardina F, Streicher E, Klopper M, Feldmann J, Müller B, Victor T, Gagneux S, Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis, in Evolution, Medicine and Public Health.
First insight into Mycobacterium tuberculosis genetic diversity and drug resistance conferring mutations in the Democratic Republic of the Congo
Fenner L, Gagneux S, Kabuya G, Stucki D, Kabuyai JP, Borrell S, Frei R, Burri C, Kalemwa D, Egger M, Okiata JP, First insight into Mycobacterium tuberculosis genetic diversity and drug resistance conferring mutations in the Democratic Republic of the Congo, in East African Med J.
M. tuberculosis strains differ in their mutation rate leading to drug resistance
Ford C, Shah R, Kato-Maeda M, Gagneux S, Murray M, Cohen T, Johnston J, Lipsitch M, Fortune S, M. tuberculosis strains differ in their mutation rate leading to drug resistance, in Nature Genetics.
Old and new selective pressures on Mycobacterium tuberculosis.
Brites Daniela, Gagneux Sebastien, Old and new selective pressures on Mycobacterium tuberculosis., in Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in i.
PolyTB: A genomic variation map for Mycobacterium tuberculosis.
Coll Francesc, Preston Mark, Guerra-Assunção José Afonso, Hill-Cawthorn Grant, Harris David, Perdigão João, Viveiros Miguel, Portugal Isabel, Drobniewski Francis, Gagneux Sebastien, Glynn Judith R, Pain Arnab, Parkhill Julian, McNerney Ruth, Martin Nigel, Clark Taane G, PolyTB: A genomic variation map for Mycobacterium tuberculosis., in Tuberculosis (Edinburgh, Scotland).

Collaboration

Group / person Country
Types of collaboration
University of Cape Town South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ifakara Health Institute Tanzania (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
MRC National Institute for Medical Research Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of California San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Makerere University Uganda (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Noguchi Memorial Insitute for Medical Research Ghana (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Stellenboch University South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Armauer Hansen Research Institute Ethiopia (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Harvard University United States of America (North America)
- Publication
Insitute for Tropical Medicine Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Fudan University China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
New York University School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Wellcome Trust Sanger Institute Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
MRC The Gambia Gambia (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Research Centre Borstel Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited oral presentation at Fortbildung für Biologielehrer, Botanisches Institute der Universität Basel Talk given at a conference Der Ursprung und die Zukunft 25.02.2014 Basel, Switzerland Gagneux Sebastien;
Invited seminar at Wellcome Trust Sanger Institute Individual talk The Cause and Consequence of Genetic Diversity inMycobacterium tuberculosis 24.01.2014 Hinxton, Great Britain and Northern Ireland Gagneux Sebastien;
Invited oral presentation at Swiss TPH Symposium on Mycobacterial Diseases and Co-Morbidities Talk given at a conference The Cause and Consequence of Genetic Diversity in 05.12.2013 Basel, Switzerland Gagneux Sebastien;
Invited oral presentation at 44th World Conference of the International Union Against Tuberculosis and Lung Disease Talk given at a conference Evolution and Demography of (Drug-susceptible) M. tuberculosis 03.11.2013 Paris, France Gagneux Sebastien;
Invited oral presentation at TB Symposium of the Royal Tropical Institute Talk given at a conference Evolution of Drug-resistantMycobacterium tuberculosis 11.10.2013 Amsterdam, Netherlands Gagneux Sebastien;
Invited oral presentation at Yearly Conference of the Infectious Disease Society of America Talk given at a conference Phylogenetic Diversity inMycobacterium tuberculosis 03.10.2013 San Francisco, United States of America Gagneux Sebastien;
Invited oral presentation at International Symposium on Systems Biology of Infections Talk given at a conference The Cause and Consequence of Genetic Diversity inMycobacterium tuberculosis 23.06.2013 Ascona, Switzerland Gagneux Sebastien;
Invited seminar at Pasteur Institute Individual talk Genome Sequencing and The Evolution of Drug-resistantM. tuberculosis 17.06.2013 Paris, France Gagneux Sebastien;
Invited oral presentation at ETHZ Symposium on Experimental Evolution Talk given at a conference Evolutionary Forces in Drug-resistant Tuberculosis 10.06.2013 Zurich, Switzerland Gagneux Sebastien;
Invited oral presentation at Yearly Conference of the Swiss Society of Infectious Diseases Talk given at a conference The Evolution and Epidemiology of Drug-resistant Tuberculosis 30.05.2013 Lugano, Switzerland Gagneux Sebastien;
Invited seminar at Bernese Colloquium on Laboratory Medicine Individual talk Genomische Epidemiologie der Tuberkulose 14.05.2013 Bern, Switzerland Gagneux Sebastien;
Invited oral presentation at International Conference on Childhood TB Talk given at a conference The Evolution of M. tuberculosis(and the need for Systems Epidemiology) 22.03.2013 Padua, Italy, Italy Gagneux Sebastien;
Invited Plenary Lecture at Keystone Conference on Tuberculosis Talk given at a conference Evolutionary Forces inMycobacterium tuberculosis 16.03.2013 Whistler, Canada, Canada Gagneux Sebastien;
Invited seminar at Wellcome Trust Sanger Institute Individual talk Evolutionary Forces inMycobacterium tuberculosis 25.01.2013 Hinxton, UK, Great Britain and Northern Ireland Gagneux Sebastien;
Invited seminar at Insitute of Social and Preventive Medicine, University of Berne Individual talk What can we learn from large-scale genome sequencing ofM. tuberculosis ? 14.01.2013 Berne, Switzerland Gagneux Sebastien;
Invited oral presentation at Conference on Pathogen Survival Strategies, Institut for Tropical Medicine Talk given at a conference The Evolution of Multidrug-resistantTuberculosis 04.12.2012 Antwerp, Belgium, Belgium Gagneux Sebastien;
Invited oral presentation at the Oxford-Stanford University joint Conference on “Big Data” Talk given at a conference Using Genetics to Understand the Global Spread ofTuberculosis 28.11.2012 Oxford, UK, Great Britain and Northern Ireland Gagneux Sebastien;
Invited oral presentation and session chair at 11th Conference on Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases Talk given at a conference Parallel Population Expansion of Mycobacterium tuberculosisand Modern Humans 31.10.2012 New Orleans, USA, United States of America Gagneux Sebastien;
Invited Plenary lecture at 11th Conference on Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases Talk given at a conference Macro- and Micro- (Co-)Evolution of Mycobacterium tuberculosis 31.10.2012 New Orelans, USA, United States of America Gagneux Sebastien;
Invited oral presentation and session chair at Wellcome Trust Conference on Genomics and Global Health Talk given at a conference Evolutionary Forces in Mycobacterium tuberculosis:Impact on Global Control 01.10.2012 Cambridge, UK, Great Britain and Northern Ireland Gagneux Sebastien;
Invited oral presentation at 1st TB Watch Symposium Talk given at a conference The Evolution of Drug-resistantM. tuberculosis:Impact on Global Control Efforts 27.09.2012 Barcelona, Spain, Spain Gagneux Sebastien;
Invited seminar at National University of Mexico Individual talk Old and NewEvolutionary Forces in Mycobacterium tuberculosis 28.08.2012 Cuernavaca, Mexico, Mexico Gagneux Sebastien;
Invited seminar at National Institutes of Health (NIH/NIAID) Talk given at a conference Strain Diversity in M. tuberculosis 17.07.2012 Bethesda, USA, United States of America Gagneux Sebastien;
Invited oral presentation at Gordon Conference: Microbial Toxins and Pathogenicity Talk given at a conference Parallel Evolution of Tuberculosis and Modern Humans 10.07.2012 New Hampshire, USA, United States of America Gagneux Sebastien;
Invited plenary lecture at Australian Society of Microbiology 2012 conference Talk given at a conference The Evolution ofMycobacterium tuberculosis:A Long History with Recent Changes 02.07.2012 Brisbane, Australia, Australia Gagneux Sebastien;
Invited oral presentation at Society for Molecular Biology and Evolution 2012 Conference Talk given at a conference Parallel Evolution ofMycobacterium tuberculosis& Modern Humans 25.06.2012 Dublin, Ireland, Ireland Gagneux Sebastien;
Invited oral presentation at Keystone Symposium: Drug Resistance and Persistence in Tuberculosis Talk given at a conference The Fitness Cost ofDrug Resistance 14.05.2012 Kampala, Uganda, Uganda Gagneux Sebastien;
Invited seminar at Centre for Public Health Research Individual talk Population Genomics &Ecology ofMycobacterium tuberculosis 21.03.2012 Valencia, Spain, Spain Gagneux Sebastien;
Invited seminar at University Hospital Basel Individual talk What We Can Learn From 200Mycobacterium tuberculosis Genomes 13.03.2012 Basel, Switzerland, Switzerland Gagneux Sebastien;
Invited seminar at Wellcome Trust Sanger Institute Individual talk Old and New Selective Forces in Mycobacterium tuberculosis 27.01.2012 Hinxton, UK, Great Britain and Northern Ireland Gagneux Sebastien;
Invited seminar at ETH Individual talk An Overview of Activities 18.01.2012 Zurich, Switzerland, Switzerland Gagneux Sebastien;
Invited seminar at Université Paul Sabatier Individual talk Old and New Selective Forces in M. tuberculosis 11.01.2012 Toulouse, France, France Gagneux Sebastien;
Invited oral presentation at International Union Against Tuberculosis and Lung Disease, 42nd World Conference Talk given at a conference Compensatory Evolution in RifR Mycobacterium tuberculosis 26.10.2011 Lille, France, France Gagneux Sebastien;
Invited oral presentation at TB Vaccine Initiative (TBVI) Symposium Talk given at a conference Host-pathogen Co-evolutionin Human TB 17.10.2011 Madrid, Spain, Spain Gagneux Sebastien;
Invited oral presentation and session chair at BioValley Science Day, Congress Centre Basel Talk given at a conference Population genomics and micro-evolution of Mycobacterium tuberculosis 20.09.2011 Basel, Switzerland, Switzerland Gagneux Sebastien;
Invited seminar at National Centre for Tuberculosis and Lung Disease Individual talk Fitness of Drug-resistant Mtb 22.07.2011 Tbilisi, Georgia, Georgia Gagneux Sebastien;
Invited oral presentation at FEMS, 4th Congress of European Microbiologists Talk given at a conference Evolutionary forces in Mycobacterium tuberculosis 28.06.2011 Geneva, Switzerland, Switzerland Gagneux Sebastien;
Honorary lecture at European Society of Mycobacteriology, 32nd Annual Congress Talk given at a conference Host-pathogen Co-evolution in Human Tuberculosis 26.06.2011 Lübeck, Germany, Germany Gagneux Sebastien;
Invited oral presentation at European Society of Mycobacteriology, 32nd Annual Congress Talk given at a conference TB Around the World(and other things we can learn from Mtb genomes…) 26.06.2011 Lübeck, Germany, Germany Gagneux Sebastien;
Invited oral presentation at Royal Society Symposium: Human evolution, migration and history revealed by genetics, immunity and infection Talk given at a conference Host-pathogen Co-evolution in Human Tuberculosis 07.06.2011 London, UK, Great Britain and Northern Ireland Gagneux Sebastien;
Inited oral presentation at American Society of Microbiology, 110th General Meeting Talk given at a conference Humans as the Drivers of M. tuberculosis Evolution 26.05.2011 San Diego, USA, United States of America Gagneux Sebastien;
Invited seminar at Pasteur Institute, Paris Individual talk Diversité et Génétique des Populations du ComplexM. tuberculosis 19.05.2011 Paris, France, France Gagneux Sebastien;
Invited seminar at Patan Academy of Health Sciences Individual talk Tuberculosis:Past, Present, and Future 06.05.2011 Kathmandu, Nepal, Nepal Gagneux Sebastien;
Invited seminar at Leprosy Mission, Nepal Individual talk Evolutionary Forces inM. tuberculosis 05.05.2011 Lele, Nepal, Nepal Gagneux Sebastien;
Invited seminar at All India Institute of Medical Sciences Individual talk Evolutionary Forces inM. tuberculosis 20.04.2011 Delhi, India, India Gagneux Sebastien;
Invited oral presentation at Workshop on MDR-TB, Institute of Medicine of the National Academy of Sciences USA Talk given at a conference Population Ecology and Genetic Evolution of M. tuberculosis 18.04.2011 Delhi, India, India Gagneux Sebastien;
Invited oral presentation at World TB Day Symposium, Institute for Tropical Medicine Talk given at a conference Linking DNA Sequence Diversity to Phenotypic Diversity inM. tuberculosis 22.03.2011 Antwerp, Belgium, Belgium Gagneux Sebastien;
Invited seminar at SysteMTb – First Workshop on TB Biology Talk given at a conference Co-evolution of M. tuberculosis with Modern Humans andDrug Resistance 21.03.2011 Prague, Czech Republic, Czech Republic Gagneux Sebastien;
Invited seminar at Institute for Social and Preventive Medicine, University of Bern Individual talk What can we learn from multipleM. tuberculosis Genomes ? 04.02.2011 Bern, Switzerland, Switzerland Gagneux Sebastien;
Invited oral presentation and session chair at Keystone Symposia: Mycobacteria: Physiology, Metabolism and Pathogenesis - Back to the Basics (J4) Talk given at a conference Co-evolution of M. tuberculosis with Modern Humans andDrug Resistance 15.01.2011 Vancouver, Canada, Canada Gagneux Sebastien;
2nd Invited oral presentation at International Union Against Tuberculosis and Lung Disease, 41st World Conference Talk given at a conference Relevance of Strain Diversity 15.11.2010 Berlin, Germany, Germany Gagneux Sebastien;
Invited oral presentation at International Union Against Tuberculosis and Lung Disease, 41st World Conference Talk given at a conference Population Genomics, Fitness, and Microevolution ofDrug Resistance 14.11.2010 Berlin, Germany, Germany Gagneux Sebastien;
Invited oral presentation and session chair at TB Symposium at Pasteur Institute of Tunis Talk given at a conference Evolutionary Forces in Mycobacterium tuberculosis 20.09.2010 Tunis, Tunisia, Tunisia Gagneux Sebastien;
Invited seminar at Unidad de Investigacion Medica Zacatecas Talk given at a conference Evolutionary Forces in Mycobacterium tuberculosis 23.08.2010 Zacatecas, Mexico, Mexico Gagneux Sebastien;
Invited seminar at Broad Institute (MIT and Harvad University) Talk given at a conference Evolutionary Forces in Mycobacterium tuberculosis 15.07.2010 Cambridge, USA, United States of America Gagneux Sebastien;
Invited oral presentation at French Society of Microbiology Meeting Talk given at a conference Evolutionary Forces in Mycobacterium tuberculosis 04.06.2010 Marseille, France, France Gagneux Sebastien;
Invited seminar at Chinese Academy of Medical Sciences Individual talk Evolutionary Forces inMycobacterium tuberculosis 14.05.2010 Beijing, China , China Gagneux Sebastien;
Invited seminar at Fudan University Individual talk Evolutionary Forces inMycobacterium tuberculosis 11.05.2010 Shanghai, China, China Gagneux Sebastien;
NIH/Howard Hugh Institute/MRC South Africa TB symposium Talk given at a conference Global Strain Diversity (a case for Evolutionary Thinking) 02.03.2010 Pretoria, South Africa, South Africa Gagneux Sebastien;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media A disease as old as humanity itself: How TB took over the world The Independent International 2013
Media relations: print media, online media Bakterien: Tuberkulose quälte Menschen schon vor 70.000 Jahren Spiegel Wissenschaft International 2013
Media relations: print media, online media TB has human, not animal, origins - says study BBC News International 2013
Media relations: print media, online media Tuberculosis followed humans out of Africa The Denver Post International 2013
Media relations: print media, online media Wie entstand die Schwindsucht? SRF German-speaking Switzerland 2013
Media relations: print media, online media Neue Einblicke in die Entstehung von Antibiotikaresistenzen Neue Zürcher Zeitung German-speaking Switzerland 2012
Media relations: print media, online media TUBERKULOSE-ERREGER IST ERSCHRECKEND FIT Bild der Wissenschaft International 2012
New media (web, blogs, podcasts, news feeds etc.) Das Erfolgsrezept des Tuberkulose-Bakteriums ... Multiresistente Erreger: Das Erfolgsrezept des Tube Focus online International 2011
Media relations: print media, online media The Evolution of Drug Resistance The Scientist International 2011
New media (web, blogs, podcasts, news feeds etc.) Warum sich resistente Tuberkulosebakterien verbreiten University of Basel Press Release German-speaking Switzerland 2011
New media (web, blogs, podcasts, news feeds etc.) Immune Evasion Common in Many Viruses, Bacteria and Parasites Is Uncommon in M. Tuberculosis Science Daily International 2010
Media relations: radio, television Tuberkulose – die neue alte Seuche Radio DRS 2 German-speaking Switzerland 2010

Awards

Title Year
Swiss TB Award for the best publication on Tuberculosis Research. 2014

Associated projects

Number Title Start Funding scheme
153442 Population genomics of drug resistant tuberculosis 01.06.2014 Project funding (Div. I-III)
150750 Integrating Genomic and Ecologic Approaches to Understand the Nature and Consequence of Genetic Diversity in Mycobacterium tuberculosis 01.03.2014 SNSF Professorships

Abstract

Tuberculosis is an urgent public health problem, but extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis are threatening global control efforts. The outcome of human infection with M. tuberculosis is extremely variable, ranging from lifelong asymptomatic infection to active pulmonary disease and extra-pulmonary tuberculosis. Traditionally, host and environmental factors have been invoked to explain this variability, but recent studies suggest that bacterial factors could also be involved. Bacterial diversity can be generated through micro-evolutionary mechanisms, such as the acquisition of drug resistance-conferring mutations. In addition, strains of a particular bacterial species can diverge as a result of separate evolutionary histories over longer time periods, leading to distinct evolutionary lineages within the species (i.e., macro-evolutionary strain diversity). Because both of these processes can generate diversity capable of affecting strain-specific phenotypic characteristics, both need to be considered to better understand the pathogenesis and epidemiology of pathogens in their natural environment. Here I propose a research program that investigates the nature and consequence of genetic diversity in M. tuberculosis from a micro- and macro-evolutionary perspective.Micro-evolution includes a process generally referred to as compensatory evolution. Compensatory mutations are genetic changes that can mitigate the negative impact on Darwinian fitness caused by a deleterious mutation in a particular genetic background. Many studies have shown that drug resistance-conferring mutations can have deleterious effects on the fitness of drug-resistant organisms. Because of this fitness “cost” associated with resistance to antimicrobials, it has been proposed that the worldwide epidemic of drug-resistance could be addressed by suspending the use of particular antimicrobials, and to let drug-susceptible strains out-compete the resistant ones. However, this strategy is unlikely to succeed because i) not all drug-resistance-conferring mutations lead to a loss of fitness, ii) particular strain lineages (i.e., genetic backgrounds) can be pre-adapted to drug-resistance, and iii) even if there is an initial fitness cost associated with a particular drug resistance-conferring mutation, compensatory evolution can mitigate the deleterious effects of the original drug resistance mutation. Importantly, studies have shown that compensatory evolution can stabilize drug resistance in bacterial populations because drug-resistant stains with compensatory mutations tend to have a higher fitness compared to strains harboring the compensatory mutation without the associated drug resistance-conferring mutation. However, most of the work on compensatory evolution and drug resistance has been undertaken in model systems, and there is a need to explore this phenomenon in clinical settings by studying relevant human pathogens, such as drug-resistant M. tuberculosis. We and others have shown that drug resistance-conferring mutations can have a variable impact on the strain fitness and transmission dynamics of M. tuberculosis. Recent data from our laboratory suggest that compensatory evolution could be occurring during treatment within a single patient. To address this possibility, we have generated laboratory-derived isogenic mutants resistant to rifampicin that were experimentally evolved to select for compensatory evolution. Here I propose to pursue this hypothesis building on my previous work. I will use comparative whole-genome sequencing and high-throughput single nucleotide polymorphism typing to identify putative compensatory mutations in the same set of laboratory-derived mutants and in a collection of clinical strains. Putative compensatory mutations will be validated by standard molecular genetic tools and fitness assays in liquid culture and macrophages.The macro-evolutionary arm of my research program addresses the inherent genetic diversity of different M. tuberculosis strain lineages. M. tuberculosis exhibits less genetic diversity compared to other bacteria, but our recent data shows that the global diversity of this pathogen has been underestimated, and that several distinct macro-evolutionary lineages can be defined within the species. Some of these strain lineages are “ancient” and others “modern” with respect to their hypothetical common ancestor. I hypothesize that ancient and modern M. tuberculosis lineages are perceived differently by the human host and that these differences will be reflected in the innate host immune response. To test this hypothesis, we will select representatives of the most common ancient and modern M. tuberculosis lineages from Tanzania. I am focusing on African strains because Africa is suffering disproportionaly from the global tuberculosis epidemic, and because information on strain diversity remains limited for this part of the world. We will generate the full genome sequences of these Tanzanian strains to identify key genomic differences between the ancient and modern strain lineages. To test whether these genomic differences impact strain phenotype, we will apply a set of phenotypic assays, including growth and fitness experiments, and cytokine and gene expression measurements in macrophages. Future research will include looking for correlates between genomic, experimental, and clinical features in ancient and modern strain lineages.The proposed research has the potential to improve our understanding of the basic biology of tuberculosis, particularly in relation to drug-resistance and host-pathogen interaction. This knowledge will contribute to the development, evaluation, and deployment of new tuberculosis control tools in Africa and elsewhere. In the light of the SystemsX initiative and ongoing mycobacterial research in Switzerland, my research program will strengthen interactions between institutions in Basel and nationwide, and promote the development and teaching of systems biology through its application to one of the most important human pathogens.
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