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Evolution and epidemiology of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town: implications for biology and disease control

Applicant Gagneux Sebastien
Number 170834
Funding scheme Bilateral programmes
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Experimental Microbiology
Start/End 01.06.2017 - 31.05.2021
Approved amount 349'828.00
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All Disciplines (2)

Discipline
Experimental Microbiology
Medical Microbiology

Keywords (8)

drug resistance; infectious disease; epidemiology; evolution; ecology; antibiotics; fitness; mycobacteria

Lay Summary (German)

Lead
Die Tuberkulose (TB) ist nach wie vor weltweit ein grosses Gesundheitsproblem, insbesondere in Südafrika. Jedes Jahr sterben weltweit 1.8 Millionen Menschen in dieser Infektionskrankheit, die vom Bakterium Mycobacterium tuberculosis (Mtb) verursacht wird. Ein besonders gravierendes Problem in der TB Behandlung, ist das vermehrte Aufkommen von Resistenzen zu mehreren Antibiotika.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Mehrfach resistente TB (MDR-TB) ist gerade in Südafrika ein ganz grosses Problem. Früher ging man davon aus, dass Antibiotikaresistezen immer de novo entstehen, d.h. während der Behandlung einzelner Patienten, z.B. weil sie ihre Medikamente nicht konsequent einnehmen. Nun wissen wir, dass dem nicht so ist und Patienten mit einer MDR-TB ihre Bakterien auch direkt an andere Personen weitergeben können. Allerdings unterscheidet sich die Uebertragbarkeit dieser MDR-TB Bakterien sehr.

Das Ziel dieses Projektes ist es, die Biologie und Epidemiologie von Antibiotikaresitenz in der TB zu erforschen. Wir wenden dafür neueste Methoden an, die auf hochauflösender Ganzgenomsequenzierung von Patienten Isolaten beruhen und einen detaillierten Blick in die bakteriellen Populationen inerhalb einzelner TB Patienten erlauben. Zusätzlich haben unsere südafrikanischen Kollegen über mehr als 10 Jahre eine grosse Stammsammlungen von TB Bakterien angelegt aus einer bestimmten Gegend in Kapstadt (Khayelitsha), wo die MDR-TB Rate besonders gross ist. Wir werden einen Teil dieser Sammlung anhand von iherer Genome analysieren, um die Merkmale, der besonders übertragbaren Formen der MDR-TB Bakterien, zu identifizieren.

 Diese Arbeiten werden in Zusammenarbeit mit unseren südafrikanischen Kollegen durchgeführ, die auch einen direkten Zugang zu TB Patienten und deren Bakterien Isolaten und klinischen Daten ermöglichen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit wird wichtige Information generieren, die zur einem besseren Verständnis der TB führen werden. Diese Ergebnisse werden u.a. für die Entwicklung besserer Diagnosemethoden und neuer Medikameneten höchst relevant sein. Gleichzeitig werden wir zusammen mit unseren südafrikanischen Kollegen bioinformatische Methoden in Südafrika etablieren und so zum Forschungspotential im Lande beitragen.

Direct link to Lay Summary Last update: 28.03.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim
Menardo Fabrizio, Rutaihwa Liliana K., Zwyer Michaela, Borrell Sonia, Comas Iñaki, Conceição Emilyn Costa, Coscolla Mireia, Cox Helen, Joloba Moses, Dou Horng-Yunn, Feldmann Julia, Fenner Lukas, Fyfe Janet, Gao Qian, García de Viedma Darío, Garcia-Basteiro Alberto L., Gygli Sebastian M., Hella Jerry, Hiza Hellen, Jugheli Levan, Kamwela Lujeko, Kato-Maeda Midori, Liu Qingyun, Ley Serej D., et al. (2021), Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim, in F1000Research, 10, 60-60.
Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history
Coscolla Mireia, Gagneux Sebastien, Menardo Fabrizio, Loiseau Chloé, Ruiz-Rodriguez Paula, Borrell Sonia, Otchere Isaac Darko, Asante-Poku Adwoa, Asare Prince, Sánchez-Busó Leonor, Gehre Florian, Sanoussi C. N’Dira, Antonio Martin, Affolabi Dissou, Fyfe Janet, Beckert Patrick, Niemann Stefan, Alabi Abraham S., Grobusch Martin P., Kobbe Robin, Parkhill Julian, Beisel Christian, Fenner Lukas, Böttger Erik C., et al. (2021), Phylogenomics of Mycobacterium africanum reveals a new lineage and a complex evolutionary history, in Microbial Genomics, 7(2), 000477.
Multiple Merger Genealogies in Outbreaks of Mycobacterium tuberculosis
Menardo Fabrizio, Gagneux Sébastien, Freund Fabian (2021), Multiple Merger Genealogies in Outbreaks of Mycobacterium tuberculosis, in Molecular Biology and Evolution, 38(1), 290-306.
A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region
Ngabonziza Jean Claude Semuto, Loiseau Chloé, Marceau Michael, Jouet Agathe, Menardo Fabrizio, Tzfadia Oren, Antoine Rudy, Niyigena Esdras Belamo, Mulders Wim, Fissette Kristina, Diels Maren, Gaudin Cyril, Duthoy Stéphanie, Ssengooba Willy, André Emmanuel, Kaswa Michel K., Habimana Yves Mucyo, Brites Daniela, Affolabi Dissou, Mazarati Jean Baptiste, de Jong Bouke Catherine, Rigouts Leen, Gagneux Sebastien, Meehan Conor Joseph, et al. (2020), A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region, in Nature Communications, 11(1), 2917-2917.
Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients
Reichmuth Martina L., Hömke Rico, Zürcher Kathrin, Sander Peter, Avihingsanon Anchalee, Collantes Jimena, Loiseau Chloé, Borrell Sonia, Reinhard Miriam, Wilkinson Robert J., Yotebieng Marcel, Fenner Lukas, Böttger Erik C., Gagneux Sebastien, Egger Matthias, Keller Peter M. (2020), Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients, in Antimicrobial Agents and Chemotherapy, 64(11), e00513.
HIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosis
Loiseau Chloé, Brites Daniela, Reinhard Miriam, Zürcher Kathrin, Borrell Sonia, Ballif Marie, Fenner Lukas, Cox Helen, Rutaihwa Liliana K., Wilkinson Robert J., Yotebieng Marcel, Carter E. Jane, Abimiku Alash'le, Marcy Olivier, Gotuzzo Eduardo, Avihingsanon Anchalee, Zetola Nicola, Doulla Basra, Böttger Erik C., Egger Matthias, Gagneux Sebastien (2020), HIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosis, in Antimicrobial Agents and Chemotherapy, 64(10), e00782.
Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis
Øyås Ove, Borrell Sonia, Trauner Andrej, Zimmermann Michael, Feldmann Julia, Liphardt Thomas, Gagneux Sebastien, Stelling Jörg, Sauer Uwe, Zampieri Mattia (2020), Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis, in Proceedings of the National Academy of Sciences, 117(15), 8494-8502.
An African origin for Mycobacterium bovis
Loiseau Chloé, Menardo Fabrizio, Aseffa Abraham, Hailu Elena, Gumi Balako, Ameni Gobena, Berg Stefan, Rigouts Leen, Robbe-Austerman Suelee, Zinsstag Jakob, Gagneux Sebastien, Brites Daniela (2020), An African origin for Mycobacterium bovis, in Evolution, Medicine, and Public Health, 2020(1), 49-59.
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 (2020), The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis, in Molecular Biology and Evolution, 37(1), 195-207.
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 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.
Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment
de Vos Margaretha, Ley Serej D., Wiggins Kristin B., Derendinger Brigitta, Dippenaar Anzaan, Grobbelaar Melanie, Reuter Anja, Dolby Tania, Burns Scott, Schito Marco, Engelthaler David M., Metcalfe John, Theron Grant, van Rie Annelies, Posey James, Warren Rob, Cox Helen (2019), Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment, in New England Journal of Medicine, 380(22), 2178-2180.
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.
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.
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.
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.
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.
TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities
Carey Allison F., Rock Jeremy M., Krieger Inna V., Chase Michael R., Fernandez-Suarez Marta, Gagneux Sebastien, Sacchettini James C., Ioerger Thomas R., Fortune Sarah M. (2018), TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities, in PLOS Pathogens, 14(3), e1006939-e1006939.
Ecology and evolution of Mycobacterium tuberculosis
Gagneux Sebastien (2018), Ecology and evolution of Mycobacterium tuberculosis, in Nature Reviews Microbiology, 16(4), 202-213.
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.

Collaboration

Group / person Country
Types of collaboration
University of Cape Town South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Tania Stadler Switzerland (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
Armauer Hansen Research Insitute Individual talk Ecology and Evolution of the M. tuberculosis Complex 19.01.2020 Addis Abeba, Ethiopia Gagneux Sebastien;
Turning the Tide on Antimicrobial Resistance Talk given at a conference The Ecology and Evolution of MDR-TB 19.11.2019 Oslo, Norway Gagneux Sebastien;
Union Conference on TB and Lung Health Talk given at a conference The Ecology and Evolution of the MTBC 31.10.2019 Hyderabad, India Gagneux Sebastien;
TBScience 2019 Conference Talk given at a conference Role of Compensatory Evolution in the Transmission of MDR-TB 30.10.2019 Hyderabad, India Gagneux Sebastien;
University of Oxford Symposium Talk given at a conference TB Treatment and Resistance 02.07.2019 Oxford, Great Britain and Northern Ireland Gagneux Sebastien;
European Society of Mycobacteriology Conference Talk given at a conference Ecology and Evolution of M. tuberculosis (and how I got interested) 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;
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;
Invited Seminar Individual talk The Ecology and Evolution of Mycobacterium tuberculosis 30.01.2019 Ifakara Health Institute, Bagamoyo, Tanzania 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 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;
Invited Seminar Individual talk Ecology and Evolution of Mycobacterium tuberculosis 26.09.2018 Institute of Evolutionary Medicine, Zurich, Switzerland Gagneux Sebastien;
Invited Seminar Individual talk Ecology and Evolution of Multidrug-resistant Mycobacterium tuberculosis 24.09.2018 Biozentrum, Basel, 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;
Invited seminar Individual talk Ecology and Evolution of Mycobacterium tuberculosis 25.05.2018 Institute for Infectious Diseases, University of Bern , Switzerland Gagneux Sebastien;
Collaboration for TB Vaccine Discovery – Bill & Melinda Gates Foundation Webinar 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 21.04.2018 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;
Invited seminar Individual talk The Ecology and Evolution of Mycobacterium tuberculosis 17.01.2018 Nanyang Technological University , Singapore Gagneux Sebastien;
Workshop on “TB ONE Health” Talk given at a conference Ecology and Evolution of the Animal-adapted MTBC Revisited 23.11.2017 Dublin, Ireland Gagneux Sebastien;
Conference of the French Society of Microbiology Talk given at a conference MTBC: un compagnon fidèle de l’hommme 09.10.2017 Paris, France Gagneux Sebastien;
Invited seminar Individual talk GENOMIQUE: Typisation des Mycobactéries 03.10.2017 University of Lausanne, Switzerland Gagneux Sebastien;
Yearly Conference of the Swiss Society of Microbiology Talk given at a conference Ecology and Evolution of Human Tuberculosis 30.08.2017 Basel, Switzerland Gagneux Sebastien;
Symposium on “Pathogen Evolution” Talk given at a conference Ecology and Evolution of Human Tuberculosis 20.07.2017 University of 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;
Invited seminar Individual talk Evolution and Epidemiology of MDR-TB 20.06.2017 VetSuisse, University of Bern, Switzerland Gagneux Sebastien;
Invited seminar Individual talk Evolution of the MTBC 16.06.2017 Pasteur Institute, Paris, France Gagneux Sebastien;


Self-organised

Title Date Place
Symposium on TB Genomics 12.05.2018 University of Cape Town, South Africa

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Symposium on Biosafety Talk 25.08.2017 Basel, Switzerland Gagneux Sebastien;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Der grösste Killer der Menschheit, die Tuberkulose, gelangt wieder vermehrt ins Land – was wir jetzt NZZ am Sonntag German-speaking Switzerland 2019
Talks/events/exhibitions Senioren Uni: Die Tuberkulose: Ursprung, Gegenwart und Zukunft German-speaking Switzerland 2019

Awards

Title Year
Gardner Middlebrook Lifetime Achievement Award 2019

Associated projects

Number Title Start Funding scheme
153442 Population genomics of drug resistant tuberculosis 01.06.2014 Project funding (Div. I-III)

Abstract

BackgroundBacteria resistant to multiple antibiotics are a growing threat for global public health and the economy. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are particular problems in many parts of the world including South Africa. Yet, little is known on the bacterial factors driving the global epidemics of MDR/XDR-TB. In the past, de novo acquisition of drug resistance determinants during patient treatment was considered the main driver of drug resistance in TB because the fitness costs associated with resistance were thought to make drug-resistant bacteria less transmissible. However, recent experimental and epidemiological data show that the fitness of drug-resistant Mycobacterium tuberculosis (Mtb) is heterogeneous and that a large proportion of MDR-TB is in fact transmitted. Preventing ongoing transmission of drug-resistant TB (DR-TB) is fundamental to controlling the epidemic. Understanding the interplay between drivers of de novo emergence and transmission of DR-TB, and the impact of treatment is key to developing new treatment regimens and ultimately improving control strategies.Aim, Hypotheses and ObjectivesWe aim to use next-generation whole genome sequencing (WGS) to study the evolution and epidemiology of DR-TB in Khayelitsha, a high HIV, TB and DR-TB burden setting in South Africa. We have access to a detailed patient-level clinical database, maintained as part of an ongoing community-based DR-TB treatment programme initiated in Khayelitsha in 2008. We propose to link these data to a biobank of stored Mtb strains held at Stellenbosch University to test the following Hypotheses:1.The transmission success of drug-resistant Mtb varies as a function of the specific combination of drug resistance-conferring mutations, compensatory mutations and strain genetic background;2.The transmission success of drug-resistant Mtb further depends on the HIV status of the host;3.The within-host evolution of Mtb populations (incl. resistance acquisition) differs in HIV-coinfected and HIV-negative TB patients;4.The within-host evolution of Mtb populations also depends on the efficacy of the treatment regimen administered.We will test these hypotheses by addressing the following objectives:Primary objectives:1.Use WGS to assess drug resistance evolution and transmission of DR-TB over time (10-years from 2008-2017) and in relation to level of drug resistance, HIV status and geographical location.2.Assess ‘within-patient’ Mtb evolution among drug-resistant strains during treatment of individual patients, focusing on resistance acquisition for existing and new TB drugs, and contrasting HIV-negative and HIV-infected individuals.3.To enhance capacity for bacterial population genomic analyses and genomic epidemiology in South Africa.Secondary objectives include:1.To assess the utility of WGS for rapid determination of drug resistance profiles and the potential for use of this data to inform individualisation of treatment. 2.To assess innate resistance to new and repurposed anti-TB drugs.MethodsThe study will be both retrospective, using clinical data and stored Mtb isolates from 2008-2015 and prospective, utilising data from the Khayelitsha programme from 2016-2017. Mtb isolates will be sub-cultured and bacterial DNA extracted in South Africa and sent to Switzerland for WGS. Data analyses will be performed in close collaboration between the teams in South Africa and Switzerland; regular visits in both directions will support these exchanges. WGS will be conducted on an estimated 1,900 isolates from patients across the 10 years of the Khayelitsha cohort, using the Illumina technology. Sequence reads will be analysed using the bioinformatics pipeline developed at the Swiss Tropical and Public Health Institute (Swiss TPH) and concurrently with the bioinformatics pipeline utilised by Stellenbosch University (SUN). Phylogenomic and population genomic methods will be used to study the bacterial population structure and diversity of Mtb isolates across and within individual patients. To assess bacterial fitness in terms of between-patient transmissibility, we will collaborate with ETH Zurich to apply phylodynamic models to the sequence data. A sub-sample of patient isolates will be selected to undergo quantitative phenotypic drug susceptibility testing to a range of key first-line and second-line anti-TB drugs. This will include the new drugs bedaquiline and delamanid, and the repurposed drug linezolid. This data will be used to assess phenotype/genotype relationships for existing, new and repurposed drugs, in addition to assessing the utility of using WGS-derived resistance profiles to individualise second-line treatment. Training and capacity buildingCapacity building is a key objective of this proposal. There is capacity for two South African PhD students within this study; one has already been identified. Both students will benefit from regular visits to Switzerland for training, and from visits from Swiss investigators to South Africa. Technology transfer will be facilitated through regular visits between Swiss and South African researchers and through the conduct of two 3-day training workshops to be held in Cape Town. These workshops will bring together researchers in the field of Mtb population genomics, genomic epidemiology and bioinformatics, and will be scheduled to coincide with visits from Swiss researchers. These workshops will be open to researchers from beyond the scope of the study, including other researchers from the University of Cape Town (UCT), SUN and the University of the Western Cape.Research impactThrough describing the role of Mtb strain diversity and evolution in the transmission of DR-TB in a high DR-TB setting, this study has the potential to dramatically improve our understanding of DR-TB epidemiology and the impact of current control strategies. In addition, as Khayelitsha is one of the pilot sites for expansion of access to new TB drugs, this study provides opportunity to study the impact of the use of these new drugs on resistance evolution. The data generated through this study also provides an opportunity to assess the feasibility and impact of using WGS for routine, rapid determination of TB drug resistance, in order to optimise and individualise second-line treatment. Finally, this study offers unique opportunities to build research capacity in bioinformatics, population genomics and genomic epidemiology of TB in South Africa. The study proposes expansion of an existing collaboration between researchers at UCT, SUN and Swiss TPH, and aims to bring a much wider circle of researchers in Cape Town together to share research and collaborate further. We aim to train and support two promising doctoral students and through them build capacity in genomic epidemiology and bioinformatics in Cape Town.
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