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Host-pathogen genomic interactions and their phenotypic impact in human tuberculosis

Applicant Gagneux Sebastien
Number 177163
Funding scheme Sinergia
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Interdisciplinary
Start/End 01.02.2018 - 31.01.2023
Approved amount 1'600'904.00
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All Disciplines (4)

Discipline
Interdisciplinary
Immunology, Immunopathology
Genetics
Experimental Microbiology

Keywords (8)

virulence; immunology; mycobacteria; epidemiology; human genetics; evolution; infectious disease; genomics

Lay Summary (German)

Lead
Die Tuberkulose (TB) ist nach wie vor weltweit ein grosses Gesundheitsproblem. Jedes Jahr sterben 1.7 Millionen Menschen in dieser Infektionskrankheit, die vom Bakterium Mycobacterium tuberculosis (Mtb) verursacht wird. Obwohl die TB unbandelt oft tödlich verläuft, unterscheidet sich der Verlauf der Krankheit bei Menschen, die sich mit Mtb infizieren, enorm. Ziel diese Projektes ist es, die Rolle der genetischen Diversität sowohl des Patienten wie auch des Bakteriums bei diesen unterschiedlichen Krankheitsverläufe zu bestimmen.
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. Die meisten Personen, die sich mit Mtb infizieren zeigen keine Symptome, bei anderen befallen die Bakterien die Lunge und bei wieder anderen werden viele unterschiedliche Organe gleichzeitig befallen. 

Das Ziel dieses Projekts ist es, die Interaktion zwischen der Diversität beim Menschen und bei den Mtb Bakterien zu erforschen und zu bestimmen, wie diese Interaktion den Verlauf der Krankheit beeinflusst. Wie verwenden dafür komplementäre Ansätze: i) ein gleichzeitiger Genomvergleich von den TB Patienten selber und von den Mtb Bakterien, mit denen sie befallen sind, ii) eine detaillierte Analyse der epidemiologischen und klinischen Daten der TB Patienten, iii) Bestimmung verschiedener Eigenschaften der Mtb Bakterien innerhalb von im Labor künstlich infizierten Wirtszellen.  Die Genomdaten der TB Patienten und deren Mtb Bakterien werden dann mit den epidemiologischen Daten und Laboreigenschaften 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 Erfolg bestimmter Mtb Varianten und die TB Empfindlichkeit gewisser Bevölkerungsgruppen aufzeigen. Diese Ergebnisse werden u.a. für die Entwicklung neuer Impfstoffe und besserer Diagnosemethoden höchst relevant sein.

Direct link to Lay Summary Last update: 11.01.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
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.
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.
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.
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited seminar at Armauer Hansen Research Insitute Individual talk Ecology and Evolution of the M. tuberculosis Complex 19.01.2020 Addis Ababa, 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;
International 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;
Invited seminar at 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 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;
Inviated seminar at Ifakara Health Institute Individual talk The Ecology and Evolution of Mycobacterium tuberculosis 30.01.2019 Bagamoyo, Tanzania Gagneux Sebastien;
International 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;
Invited seminar at Institute of Evolutionary Medicine Individual talk Ecology and Evolution of Mycobacterium tuberculosis 26.09.2018 Zurich, Switzerland Gagneux Sebastien;
Invited seminar at Biozentrum, Basel Individual talk Ecology and Evolution of Multidrug-resistant Mycobacterium tuberculosis 24.09.2018 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 at Institute for Infectious Diseases, University of Bern Individual talk Ecology and Evolution of Mycobacterium tuberculosis 25.05.2018 Bern, Switzerland Gagneux Sebastien;
Invited webinar at 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;
Symposium at University of Cape Town Talk given at a conference Ecology and Evolution of the M. tuberculosis Complex 12.05.2018 Capte Town, South Africa 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;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Lecture at Senioren Uni, University of Basel German-speaking Switzerland 2019
Media relations: print media, online media Wissen NZZ am Sonntag Western Switzerland 2019

Awards

Title Year
The Gardner Middlebrook Award for Lifetime Achievement in mycobacteriology 2019

Associated projects

Number Title Start Funding scheme
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)
166687 Integrating population and functional genomics with molecular epidemiology to explore the interaction between host and pathogen diversity in human tuberculosis 01.04.2016 Project funding (Div. I-III)

Abstract

Human tuberculosis (TB) remains a global public health problem and the main cause of human death due to an infectious disease. TB is caused by a group of closely related bacteria known as the Mycobacterium tuberculosis Complex (MTBC). The outcome of TB infection and disease is highly variable, ranging from rapid bacterial clearance by innate immunity and life-long asymptomatic latent infection to active pulmonary- and extra-pulmonary disease. This variation has traditionally been attributed to host and environmental factors. Indeed, early twin studies have demonstrated a high degree of heritability in TB susceptibility. However, more recent human genetic studies have largely failed to identify TB susceptibility loci reproducibly. The limited success of these studies partially stems from the fact that the role of human variation has rarely been studied together with pathogen variation. The human-adapted MTBC is an obligate human pathogen with no animal or environmental reservoir that has affected humankind for thousands of years. Hence, co-evolution between humans and the human-adapted MTBC is likely to have contributed to some of the characteristics of the host-pathogen interactions in human TB. This notion is supported by evidence for local adaptation of different MTBC genotypes to particular human populations that are perturbed by HIV co-infection. However, formal demonstration of host-pathogen co-evolution in human TB is lacking. Moreover, no study to date has explored the combined effects of human- and MTBC genomic variation on clinically relevant phenotypes. The goal of this project is to test for genetic and functional evidence of host-pathogen co-evolution in human TB, and explore the joint effects of human and pathogen variation on ex vivo and in clinico phenotypes, including those associated with virulence and disease severity, immunogenicity, patient outcome, and bacterial transmission. We hypothesize that i) paired human- and MTBC genome data from TB patients exhibit signals of host-pathogen co-evolution that are perturbed by HIV co-infection, ii) MTBC genomic variation is driven by specific human genomic variation in TB patients (and/or vice versa), iii) MTBC virulence and transmission phenotypes measured ex vivo and in clinico vary as a function of the particular combination of human- and bacterial genotypes, and iv) specific interacting host- and bacterial genomic loci are associated with these phenotypic differences. We will test these hypotheses by addressing the following three Specific Objectives:1)Detect and characterize signals of host-pathogen co-evolution in the paired genome-wide diversity data from HIV-negative and HIV-coinfected TB patients and their cognate MTBC strains from Tanzania;2)Identify and validate interacting genomic loci in the paired genomes of TB patients and their MTBC isolates associated with ex vivo, in clinico and epidemiological phenotypes;3)Measure the virulence, immunogenicity and transmission of TB in Tanzanian patients as a function of human- and MTBC genomic diversity.This projects benefits from the multidisciplinary and complementary expertise of the study team, and from access to an ongoing cohort of TB patients in Dar es Salaam, Tanzania that is separately funded. Through this cohort, we have access to 1,200 TB patients who have already been recruited and consented, as well as to the relevant patient information, blood samples for human genomic studies, their MTBC isolates and genome sequences. In addition to analyzing these retrospective data, we will get access to samples from 650 prospectively recruited TB patients during the first two years of the project, and perform additional assays to validate and complement the findings from the retrospective analyses. These assays include measuring the Molecular Bacterial Load in sputum at the time of diagnosis, a TAM-TB assay to measure the level of immune activation, and a set of ex vivo macrophage infection experiments. The quantitative read-outs of these assays will be combined with the corresponding human- and MTBC genomic information to identify host-pathogen interacting loci that together influence these phenotypes. Our study will provide new genomic and functional insights into the role of host-pathogen co-evolution, and the relevance of both human- and bacterial variation in the biology and epidemiology of one of humankind’s most devastating diseases.
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