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Integrating population and functional genomics with molecular epidemiology to explore the interaction between host and pathogen diversity in human tuberculosis

English title Integrating population and functional genomics with molecular epidemiology to explore the interaction between host and pathogen diversity in human tuberculosis
Applicant Gagneux Sebastien
Number 166687
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Experimental Microbiology
Start/End 01.04.2016 - 30.09.2019
Approved amount 756'000.00
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All Disciplines (6)

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

Keywords (12)

molecular epidemiology; co-infection; mycobacteria; fitness; proteomics; innate immunity; virulence; population genetics; gene expression; RNAseq; coevolution; gene expression

Lay Summary (German)

Lead
Die Tuberkulose (TB) ist nach wie vor weltweit ein grosses Gesundheitsproblem. Jedes Jahr sterben 1.5 Millionen Menschen in dieser Infektionskrankheit, die vom Bakterium Mycobacterium tuberculosis (Mtb) verursacht wird. Mtb befällt den Menschen schon seit tausenden von Jahren. Allerdings ist unklar, ob und wie diese lange Koevolution zwischen dem Wirt und dem Erreger für die Bekämpfung der TB relevant ist.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Mtb hat sich über Jahrtausende an das Immunsystem des Menschen angepasst. Umgekehrt hat sich das Wirtsimmunsystem so stark entwickelt, dass eine Infektion mit Mtb bei den meisten Personen keine Symptome herbeiruft. Gewisse Personen sind allerdings mehr TB empfindlich als andere, und auch die Mtb Bakterien unterscheiden sich. Gewisse Mtb Varianten sind ansteckender als andere und kommen in der Welt auch viel häufiger vor als weniger erfolgreiche Varianten.

Das Ziel dieses Projekts ist es, die Interaktion zwischen der Diversität beim Menschen und bei den Mtb Bakterien zu erforschen. Wie verwenden dafür komplementäre Ansätze: i) ein Genomvergleich einer grosser Anzahl von Mtb klinischen Isolaten, die von TB Patienten aus aller Welt stammen, ii) eine gemeinsame Bestimmung der Genexpression von Mtb klinischen Isolaten und menschlichen Makrophagen, die mit diesen Mtb Isolaten infiziert worden sind, und iii) eine detaillierte Analyse der epidemiologischen und klinischen Daten von TB Patienten in Tansania.  Die Genomdaten werden dann mit den Genexpressionsdaten und epidemiologischen Daten integriert.

 Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit wird wichtige Information generieren, die zur einem besseren Verständnis der TB führen wird. Im speziellen werden wir diejenigen Teile des Mtb Genomes identifizieren, die mit dem menschlichen Immunsystem in Wechselwirkung stehen und mögliche Grundlagen für den globalen Erfolg bestimmter Mtb Varianten aufzeigen. Diese Ergebnisse werden u.a. für die Entwicklung neuer Impfstoffe und besserer Diagnosemethoden höchst relevant sein.

Direct link to Lay Summary Last update: 29.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Classifying recurrent Mycobacterium tuberculosis cases in Georgia using MIRU-VNTR typing
Maghradze Nino, Jugheli Levan, Borrell Sonia, Tukvadze Nestani, Aspindzelashvili Rusudan, Avaliani Zaza, Reither Klaus, Gagneux Sebastien (2019), Classifying recurrent Mycobacterium tuberculosis cases in Georgia using MIRU-VNTR typing, in PLOS ONE, 14(10), e0223610-e0223610.
The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis
Castro Rhastin A D, Ross Amanda, Kamwela Lujeko, Reinhard Miriam, Loiseau Chloé, Feldmann Julia, Borrell Sonia, Trauner Andrej, Gagneux Sebastien (2019), The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis, in Molecular Biology and Evolution, msz214.
The molecular clock of Mycobacterium tuberculosis
Menardo Fabrizio, Duchêne Sebastian, Brites Daniela, Gagneux Sebastien (2019), The molecular clock of Mycobacterium tuberculosis, in PLOS Pathogens, 15(9), e1008067-e1008067.
Revised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate Mycobacterium canettii and Members of the Mycobacterium tuberculosis Complex
Loiseau Chloé, Brites Daniela, Moser Irmgard, Coll Francesc, Pourcel Christine, Robbe-Austerman Suelee, Escuyer Vincent, Musser Kimberlee A., Peacock Sharon J., Feuerriegel Silke, Kohl Thomas A., Niemann Stefan, Gagneux Sebastien, Köser Claudio U. (2019), Revised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate Mycobacterium canettii and Members of the Mycobacterium tuberculosis Complex, in Antimicrobial Agents and Chemotherapy, 63(6), e00159-19.
Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis
Payne Joshua L., Menardo Fabrizio, Trauner Andrej, Borrell Sonia, Gygli Sebastian M., Loiseau Chloe, Gagneux Sebastien, Hall Alex R. (2019), Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis, in PLOS Biology, 17(5), e3000265-e3000265.
Whole-Genome Sequencing for Drug Resistance Profile Prediction in Mycobacterium tuberculosis
Gygli Sebastian M., Keller Peter M., Ballif Marie, Blöchliger Nicolas, Hömke Rico, Reinhard Miriam, Loiseau Chloé, Ritter Claudia, Sander Peter, Borrell Sonia, Collantes Loo Jimena, Avihingsanon Anchalee, Gnokoro Joachim, Yotebieng Marcel, Egger Matthias, Gagneux Sebastien, Böttger Erik C. (2019), Whole-Genome Sequencing for Drug Resistance Profile Prediction in Mycobacterium tuberculosis, in Antimicrobial Agents and Chemotherapy, 63(4), e02175-18.
Multiple Introductions of Mycobacterium tuberculosis Lineage 2–Beijing Into Africa Over Centuries
Rutaihwa Liliana K., Menardo Fabrizio, Stucki David, Gygli Sebastian M., Ley Serej D., Malla Bijaya, Feldmann Julia, Borrell Sonia, Beisel Christian, Middelkoop Kerren, Carter E. Jane, Diero Lameck, Ballif Marie, Jugheli Levan, Reither Klaus, Fenner Lukas, Brites Daniela, Gagneux Sebastien (2019), Multiple Introductions of Mycobacterium tuberculosis Lineage 2–Beijing Into Africa Over Centuries, in Frontiers in Ecology and Evolution, 7, 112.
Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania
Rutaihwa Liliana K., Sasamalo Mohamed, Jaleco Aladino, Hella Jerry, Kingazi Ally, Kamwela Lujeko, Kingalu Amri, Malewo Bryceson, Shirima Raymond, Doetsch Anna, Feldmann Julia, Reinhard Miriam, Borrell Sonia, Brites Daniela, Reither Klaus, Doulla Basra, Fenner Lukas, Gagneux Sebastien (2019), Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania, in PLOS ONE, 14(4), e0206334-e0206334.
Reference set of Mycobacterium tuberculosis clinical strains: A tool for research and product development
Borrell Sònia, Trauner Andrej, Brites Daniela, Rigouts Leen, Loiseau Chloe, Coscolla Mireia, Niemann Stefan, De Jong Bouke, Yeboah-Manu Dorothy, Kato-Maeda Midori, Feldmann Julia, Reinhard Miriam, Beisel Christian, Gagneux Sebastien (2019), Reference set of Mycobacterium tuberculosis clinical strains: A tool for research and product development, in PLOS ONE, 14(3), e0214088-e0214088.
Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries: a multicentre cohort study
Zürcher Kathrin, Ballif Marie, Fenner Lukas, Borrell Sonia, Keller Peter M, Gnokoro Joachim, Marcy Olivier, Yotebieng Marcel, Diero Lameck, Carter E Jane, Rockwood Neesha, Wilkinson Robert J, Cox Helen, Ezati Nicholas, Abimiku Alash'le G, Collantes Jimena, Avihingsanon Anchalee, Kawkitinarong Kamon, Reinhard Miriam, Hömke Rico, Huebner Robin, Gagneux Sebastien, Böttger Erik C, Egger Matthias, et al. (2019), Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries: a multicentre cohort study, in The Lancet Infectious Diseases, 19(3), 298-307.
Comparative genomics of Mycobacterium africanum Lineage 5 and Lineage 6 from Ghana suggests distinct ecological niches
Otchere Isaac Darko, Coscollá Mireia, Sánchez-Busó Leonor, Asante-Poku Adwoa, Brites Daniela, Loiseau Chloe, Meehan Conor, Osei-Wusu Stephen, Forson Audrey, Laryea Clement, Yahayah Abdallah Iddrisu, Baddoo Akosua, Ansa Gloria Akosua, Aboagye Samuel Yaw, Asare Prince, Borrell Sonia, Gehre Florian, Beckert Patrick, Kohl Thomas A., N’dira Sanoussi, Beisel Christian, Antonio Martin, Niemann Stefan, de Jong Bouke C., et al. (2018), Comparative genomics of Mycobacterium africanum Lineage 5 and Lineage 6 from Ghana suggests distinct ecological niches, in Scientific Reports, 8(1), 11269-11269.
Treemmer: a tool to reduce large phylogenetic datasets with minimal loss of diversity
Menardo Fabrizio, Loiseau Chloé, Brites Daniela, Coscolla Mireia, Gygli Sebastian M., Rutaihwa Liliana K., Trauner Andrej, Beisel Christian, Borrell Sonia, Gagneux Sebastien (2018), Treemmer: a tool to reduce large phylogenetic datasets with minimal loss of diversity, in BMC Bioinformatics, 19(1), 164-164.
Tuberculosis outbreak investigation using phylodynamic analysis
Kühnert Denise, Coscolla Mireia, Brites Daniela, Stucki David, Metcalfe John, Fenner Lukas, Gagneux Sebastien, Stadler Tanja (2018), Tuberculosis outbreak investigation using phylodynamic analysis, in Epidemics, 25, 47-53.
Tuberculosis outbreak investigation using phylodynamic analysis
Kühnert Denise, Coscolla Mireia, Brites Daniela, Stucki David, Metcalfe John, Fenner Lukas, Gagneux Sebastien, Stadler Tanja (2018), Tuberculosis outbreak investigation using phylodynamic analysis, in Epidemics, 25, 47-53.
A New Phylogenetic Framework for the Animal-Adapted Mycobacterium tuberculosis Complex
Brites Daniela, Loiseau Chloé, Menardo Fabrizio, Borrell Sonia, Boniotti Maria Beatrice, Warren Robin, Dippenaar Anzaan, Parsons Sven David Charles, Beisel Christian, Behr Marcel A., Fyfe Janet A., Coscolla Mireia, Gagneux Sebastien (2018), A New Phylogenetic Framework for the Animal-Adapted Mycobacterium tuberculosis Complex, in Frontiers in Microbiology, 9, 2820.
Ecology and evolution of Mycobacterium tuberculosis
Gagneux Sebastien (2018), Ecology and evolution of Mycobacterium tuberculosis, in Nature Reviews Microbiology, 16(4), 202-213.
The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes
Bastos Helder Novais, Osório Nuno S., Gagneux Sebastien, Comas Iñaki, Saraiva Margarida (2018), The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes, in Frontiers in Immunology, 8, 1948.
The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy
Trauner Andrej, Liu Qingyun, Via Laura E., Liu Xin, Ruan Xianglin, Liang Lili, Shi Huimin, Chen Ying, Wang Ziling, Liang Ruixia, Zhang Wei, Wei Wang, Gao Jingcai, Sun Gang, Brites Daniela, England Kathleen, Zhang Guolong, Gagneux Sebastien, Barry Clifton E., Gao Qian (2017), The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy, in Genome Biology, 18(1), 71-71.
Tuberculosis in Swiss captive Asian elephants: microevolution of Mycobacterium tuberculosis characterized by multilocus variable-number tandem-repeat analysis and whole-genome sequencing
Ghielmetti Giovanni, Coscolla Mireia, Ruetten Maja, Friedel Ute, Loiseau Chloé, Feldmann Julia, Steinmetz Hanspeter W., Stucki David, Gagneux Sebastien (2017), Tuberculosis in Swiss captive Asian elephants: microevolution of Mycobacterium tuberculosis characterized by multilocus variable-number tandem-repeat analysis and whole-genome sequencing, in Scientific Reports, 7(1), 14647-14647.
Strain Variation in the Mycobacterium tuberculosis Complex: Its Role in Biology, Epidemiology and Control
Brites Daniela, Gagneux Sebastien (2017), Strain Variation in the Mycobacterium tuberculosis Complex: Its Role in Biology, Epidemiology and Control, Springer International Publishing, Cham.
The Influence of HIV on the Evolution of Mycobacterium tuberculosis
Koch Anastasia S., Brites Daniela, Stucki David, Evans Joanna C., Seldon Ronnett, Heekes Alexa, Mulder Nicola, Nicol Mark, Oni Tolu, Mizrahi Valerie, Warner Digby F., Parkhill Julian, Gagneux Sebastien, Martin Darren P., Wilkinson Robert J. (2017), The Influence of HIV on the Evolution of Mycobacterium tuberculosis, in Molecular Biology and Evolution, 34(7), 1654-1668.
Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives
Gygli Sebastian M., Borrell Sonia, Trauner Andrej, Gagneux Sebastien (2017), Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives, in FEMS Microbiology Reviews, 41(3), 354-373.
Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages
Stucki David, Brites Daniela, Jeljeli Leïla, Coscolla Mireia, Liu Qingyun, Trauner Andrej, Fenner Lukas, Rutaihwa Liliana, Borrell Sonia, Luo Tao, Gao Qian, Kato-Maeda Midori, Ballif Marie, Egger Matthias, Macedo Rita, Mardassi Helmi, Moreno Milagros, Vilanova Griselda Tudo, Fyfe Janet, Globan Maria, Thomas Jackson, Jamieson Frances, Guthrie Jennifer L, Asante-Poku Adwoa, et al. (2016), Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages, in Nature Genetics, 48(12), 1535-1543.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
University of Oxford Individual talk TB Treatment and Resistance 02.07.2019 Oxford, Great Britain and Northern Ireland Gagneux Sebastien;
European Society of Mycobacteriology Talk given at a conference Middelbrook-Award Lecture 30.06.2019 Valencia, Spain Gagneux Sebastien;
National Centre for Tuberculosis and Lung Diseases, Fogarty Symposium Talk given at a conference Ecology and Evolution of MDR M. tuberculosis 05.06.2019 Lopota, Georgia Gagneux Sebastien;
University of Cape Town Individual talk Ecology and Evolution of the M. tuberculosis Complex 12.05.2019 Cape Town, South Africa Gagneux Sebastien;
Union Conference on TB and Lung Health, North-American Region Talk given at a conference Population Genomics of the M. tuberculosis Complex 21.02.2019 Vancouver, Canada Gagneux Sebastien;
Ifakara Health Institute Individual talk The Ecology and Evolution of Mycobacterium tuberculosis 30.01.2019 Bagamoyo, Tanzania Gagneux Sebastien;
Workshop on “TB ONE Health” Talk given at a conference Ecology and Evolution of the Animal-adapted MTBC Revisited 23.11.2018 Dublin, Ireland Gagneux Sebastien;
Union Conference on TB and Lung Health Talk given at a conference A History of the Microbe: Co-evolution of Humans/Animals and TB 26.10.2018 The Hague, Netherlands Gagneux Sebastien;
TBScience 2018 Conference Talk given at a conference WGS To Quantify MDR-TB Transmission 23.10.2018 The Hague, Netherlands Gagneux Sebastien;
International Conference on Clinical Metagenomics Talk given at a conference WGS To Quantify MDR-TB Transmission 18.10.2018 Geneva, Switzerland Gagneux Sebastien;
Institute of Evolutionary Medicine Individual talk Ecology and Evolution of Mycobacterium tuberculosis 26.09.2018 Zurich, Switzerland Gagneux Sebastien;
Biozenrtrum, University of Basel Individual talk Ecology and Evolution of Multidrug-resistant Mycobacterium tuberculosis 24.09.2018 Biozentrum, Switzerland Gagneux Sebastien;
Bilbo TB Conference Talk given at a conference Ecology and Evolution of (MDR) Mycobacterium tuberculosis 17.09.2018 Bilbao, Spain Gagneux Sebastien;
International Symposium on Antibiotic Resistance Talk given at a conference Epistasis and Compensatory Evolution in Multidrug-resistant Mycobacterium tuberculosis 30.05.2018 Stockholm, Sweden Gagneux Sebastien;
Institute for Infectious Diseases, University of Bern Individual talk Ecology and Evolution of Mycobacterium tuberculosis 25.05.2018 Bern, Switzerland Gagneux Sebastien;
Collaboration for TB Vaccine Discovery – Bill & Melinda Gates Foundation Individual talk Population genomics of M. tuberculosis and implications for product development 24.05.2018 Seattle, United States of America Gagneux Sebastien;
28th European Congress of Clinical Microbiology and Infectious Diseases Talk given at a conference Clinical Relevance of Genetic Diversity in M. tuberculosis 24.04.2018 Madrid, Spain Gagneux Sebastien;
International Symposium on “Inflammation at Interfaces” Talk given at a conference Genome Evolution of Mycobacterium tuberculosis 26.03.2018 Hamburg, Germany Gagneux Sebastien;
Nanyang Technological University Individual talk The Ecology and Evolution of Mycobacterium tuberculosis 16.01.2018 Singapore, Singapore Gagneux Sebastien;
University Hospital, Lausanne Individual talk GENOMIQUE: Typisation des Mycobactéries 03.10.2017 Lausanne, Switzerland Gagneux Sebastien;
Yearly Conference of the Swiss Society of Microbiology Talk given at a conference Ecology and Evolution of Human Tuberculosis 01.09.2017 Basel, Switzerland Gagneux Sebastien;
Swiss Network of Biosafety Talk given at a conference Multidrug-Resistant Tuberculosis: A Threat to Global Public Health 25.08.2017 Basel, Switzerland Gagneux Sebastien;
Symposium on “Pathogen Evolution” Talk given at a conference Ecology and Evolution of Human Tuberculosis 20.07.2017 Kiel, Germany Gagneux Sebastien;
Yearly Conference of the European Society of Mycobacteriology Talk given at a conference Population Structure and Transmission of the MTBC 26.06.2017 Sibenik, Croatia Gagneux Sebastien;
VetSuisse, University of Bern Individual talk Evolution and Epidemiology of MDR-TB 20.06.2017 Bern, Switzerland Gagneux Sebastien;
Pasteur Institute Individual talk Evolution of the MTBC 16.06.2017 Paris, France Gagneux Sebastien;
University of Toulouse Individual talk The Cause and Consequence of Genetic Diversity in Mycobacterium tuberculosis 24.04.2017 Toulouse, France Gagneux Sebastien;
10th National Conference on Laboratory Aspects of Tuberculosis Talk given at a conference Evolution of MDR-TB 19.04.2017 Atlanta, United States of America Gagneux Sebastien;
Symposium on “Future of Health”, Institute of Systems Biology Talk given at a conference Evolution of Human TB: Implications for Global Control 03.04.2017 Seattle, United States of America Gagneux Sebastien;
TB Symposium Talk given at a conference A Joint History of TB and Humankind 23.03.2017 Magglingen, Switzerland Gagneux Sebastien;
Lecture at Biozentrum, Universty of Basel Individual talk Evolution of Multidrug-resistant Tuberculosis 21.11.2016 Basel, Switzerland Gagneux Sebastien;
Congress of the Latin-American Society of Mycobacteria Talk given at a conference Evolution and Epidemiology of MDR-TB 29.09.2016 Rosario, Argentina Gagneux Sebastien;
Congress of the Latin-American Society of Microbiology Talk given at a conference Coevolution of M. tuberculosis and H. sapiens 27.09.2016 Rosario, Argentina Gagneux Sebastien;
EMBO Conference on Tuberculosis, Pasteur Institute Talk given at a conference Generalists and Specialists in M. tuberculosis 20.09.2016 Paris, France Gagneux Sebastien;
Lecture at Ifakara Health Institute Individual talk Evolution of Human Tuberculosis: Implications for Disease Control 11.08.2016 Ifakara, Tanzania Gagneux Sebastien;
TB2016, International AIDS Society Conference Talk given at a conference Evolution and Spread of Drug Resistance 17.07.2016 Durban, South Africa Gagneux Sebastien;
Mini Symposium at Roche Pharmaceuticals Talk given at a conference Evolution and Ecology of Multidrug-resistant Tuberculosis 28.06.2016 Basel, Switzerland Gagneux Sebastien;
Lecture at McGill University Individual talk Evolution of Human Tuberculosis 23.06.2016 Montreal, Canada Gagneux Sebastien;
Lecture at Infectious Disease Seminar, University Hospital Basel Individual talk Evolution and Epidemiology of Multidrug-resistant Tuberculosis 31.05.2016 Basel, Switzerland Gagneux Sebastien;
Lecture at Pasteur Insitute Individual talk Evolution and Epidemiology of Multidrug-resistant Tuberculosis 27.05.2016 Paris, France Gagneux Sebastien;
Congress of the African Society of Human Genetics Talk given at a conference Evolution of Human Tuberculosis 15.05.2016 Dakar, Senegal Gagneux Sebastien;
Congress of the European Society of Medical Microbiology and Infectious Diseases Talk given at a conference Personalized Medicine in Tuberculosis 11.04.2016 Amsterdam, Netherlands Gagneux Sebastien;
Symposium at Critical Path Institute Talk given at a conference Acquired Resistance to New TB Drugs: Insights for Diagnostics and Treatment 07.04.2016 Washington DC, United States of America Gagneux Sebastien;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions 2. Symposium of Swiss Science Journalists on Evolutionary Medicine German-speaking Switzerland 2016
Talks/events/exhibitions Lecture at Stiftung Solidarität Dritte Welt German-speaking Switzerland 2016

Awards

Title Year
Gardner Middlebrook Lifetime Achievement Award 2019

Associated projects

Number Title Start Funding scheme
164171 Mixed strain infections in human tuberculosis: their role in biology, epdemiology and clinical outcome 01.09.2016 Bilateral programmes
188888 Population genomic and phenotypic determinants of host tropism in the Mycobacterium tuberculosis Complex affecting livestock and humans 01.10.2019 Project funding (Div. I-III)
177163 Host-pathogen genomic interactions and their phenotypic impact in human tuberculosis 01.02.2018 Sinergia

Abstract

Tuberculosis (TB) remains a global public health emergency with 1.5 million people dying from the disease every year. TB is caused by a group of closely related bacteria known as the Mycobacterium tuberculosis complex (MTBC). The global TB epidemic is made worse by the emergence of MTBC strains resistant to multiple antibiotics and the lack of an effective vaccine. The outcome of TB infection and disease is highly variable ranging from latent infection to pulmonary and extrapulmonary disease. To date, most of the work on host-pathogen interaction in TB has focused on patient and environmental variables, neglecting the phylogenetic diversity of MTBC clinical strains. Yet, an increasing number of experimental studies demonstrate that MTBC clinical strains differ in virulence and immunogenicity, and epidemiological studies show that these strains also differ in transmissibility. However, linking experimental phenotypes to relevant clinical outcomes in patient populations has proven difficult. Because the MTBC has co-evolved with humans for thousands of years, human and MTBC diversity will likely interact in shaping the epidemiology of TB. In support of this view, we and others have shown using molecular epidemiological approaches that sympatric associations between some MTBC genotypes and their respective human host populations remain stable over time. This is consistent with a specialist phenotype in which MTBC variants have adapted to particular human populations. Other MTBC genotypes occur worldwide, consistent with a generalist phenotype capable of infecting many different human populations. Both generalist and specialist MTBC strains are epidemiologically successful on their own right, which is in contrast to many unsuccessful strains that are generally rare and exhibit a reduced transmission potential. Here we propose to pursue these epidemiological observations experimentally, taking advantage of our ongoing TB patient cohort (TB-DAR) in Dar es Salaam, Tanzania. The overall goal of this project is to define the detailed population structure and phylogenomic diversity of the MTBC circulating in Dar es Salaam, the evolutionary forces driving this diversity, and its phenotypic consequences as a function of the associated host diversity. We hypothesise that i) the epidemiological success of generalist versus specialist versus unsuccessful MTBC clinical strains differs as a function of the phylogenetic strain background and the human host population, ii) these differences in epidemiological success are reflected in signatures of selection in the MTBC genome, iii) in experimental phenotypes, and iv) in different demographic, clinical and epidemiological characteristics. We will test these hypotheses by addressing the following three main Objectives:1.Analyse the population structure, genomic diversity and signatures of selection in MTBC clinical strains circulating in Dar es Salaam compared to the national and global MTBC diversity.2.Characterise the phenotypic consequences of MTBC diversity following infection of human macrophages as a function of host variation in Tanzania.3.Link MTBC population genomic data (Objective 1) to phenotypic data obtained experimentally (Objective 2) with epidemiological data collected through the TB-DAR cohort.We will take an integrated multidisciplinary approach and combine i) in-depth population genomic analyses of MTBC clinical strains from the TB-DAR cohort compared to our global collection of ~20,000 MTBC genome sequences, ii) dual RNAseq and dual proteomics analyses of TB patient-derived macrophages infected with matched and miss-matched MTBC clinical strains, iii) intracellular bacterial growth assays, iv) cytokine/chemokine measurements of infected macrophages, v) genomic epidemiological analyses of TB transmission, and vi) detailed clinical and epidemiological data collected through the TB-DAR cohort. Importantly, we will be able to correlate MTBC genomic diversity with experimental and clinical phenotypic diversity because all our genomic, functional and epidemiological data will be linked to individual TB patients. This approach will generate new insights into the genomic diversity and molecular evolution of the MTBC, as well as into the cross-talk between MTBC diversity and host innate immunity in different human genetic backgrounds. Ultimately, this project will improve our understanding of the biology of host-pathogen interaction in TB, so far mainly obtained through model systems, by focusing on human macrophages and MTBC clinical isolates from well-characterised TB patients studied in a well-defined epidemiological context.
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