Article | Published:

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Nature Genetics volume 48, pages 15351543 (2016) | Download Citation

Abstract

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.

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Acknowledgements

We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.).

Author information

Author notes

    • David Stucki
    • , Daniela Brites
    •  & Leïla Jeljeli

    These authors contributed equally to this work.

Affiliations

  1. Swiss Tropical and Public Health Institute, Basel, Switzerland.

    • David Stucki
    • , Daniela Brites
    • , Mireia Coscolla
    • , Andrej Trauner
    • , Lukas Fenner
    • , Liliana Rutaihwa
    • , Sonia Borrell
    • , Marie Ballif
    • , Bijaya Malla
    • , Serej D Ley
    • , Hans-Peter Beck
    •  & Sebastien Gagneux
  2. University of Basel, Basel, Switzerland.

    • David Stucki
    • , Daniela Brites
    • , Mireia Coscolla
    • , Andrej Trauner
    • , Lukas Fenner
    • , Liliana Rutaihwa
    • , Sonia Borrell
    • , Marie Ballif
    • , Bijaya Malla
    • , Serej D Ley
    • , Hans-Peter Beck
    •  & Sebastien Gagneux
  3. Forschungszentrum Borstel, Borstel, Germany.

    • Leïla Jeljeli
    •  & Stefan Niemann
  4. Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia.

    • Leïla Jeljeli
    •  & Helmi Mardassi
  5. Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

    • Qingyun Liu
    •  & Qian Gao
  6. Institute for Social and Preventive Medicine, University of Bern, Bern, Switzerland.

    • Lukas Fenner
    • , Marie Ballif
    •  & Matthias Egger
  7. Laboratory of Infection and Immunity, School of Basic Medical Science, West China Center of Medical Sciences, Sichuan University, Chengdu, China.

    • Tao Luo
  8. School of Medicine, University of California at San Francisco, San Francisco, California, USA.

    • Midori Kato-Maeda
  9. Laboratório de Saúde Pública, Lisbon, Portugal.

    • Rita Macedo
  10. Hospital Nossa Senhora da Paz, Cubal, Angola.

    • Milagros Moreno
  11. Servei de Microbiologia, Hospital Clínic–ISGlobal, Barcelona, Spain.

    • Griselda Tudo Vilanova
  12. Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.

    • Janet Fyfe
    •  & Maria Globan
  13. Ifakara Health Institute, Bagamoyo, Tanzania.

    • Jackson Thomas
  14. Public Health Ontario, Toronto, Ontario, Canada.

    • Frances Jamieson
    •  & Jennifer L Guthrie
  15. Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.

    • Adwoa Asante-Poku
    •  & Dorothy Yeboah-Manu
  16. Department of Medical Microbiology, Makerere University, Kampala, Uganda.

    • Eddie Wampande
    • , Willy Ssengooba
    •  & Moses Joloba
  17. Department of Global Health, University of Amsterdam, Amsterdam, the Netherlands.

    • Willy Ssengooba
  18. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA.

    • W Henry Boom
  19. LabPlus, Auckland City Hospital, Auckland, New Zealand.

    • Indira Basu
    •  & James Bower
  20. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.

    • Margarida Saraiva
  21. ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães, Portugal.

    • Margarida Saraiva
  22. Oswaldo Cruz Institute, Rio de Janeiro, Brazil.

    • Sidra E G Vasconcellos
    •  & Philip Suffys
  23. Institute of Infectious Disease and Molecular Medicine, and Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa.

    • Anastasia Koch
    • , Robert Wilkinson
    •  & Linda Gail-Bekker
  24. Department of Medicine, Imperial College London, London, UK.

    • Robert Wilkinson
  25. Francis Crick Institute Mill Hill Laboratory, London, UK.

    • Robert Wilkinson
  26. Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.

    • Serej D Ley
  27. Insitute of Tropical Medicine, Antwerp, Belgium.

    • Bouke C de Jong
    • , Florian Gehre
    •  & Suriya Akter
  28. Tartu University Hospital United Laboratories, Mycobacteriology, Tartu, Estonia.

    • Kadri Toit
  29. Clinical Research Department, Epicentre, Paris, France.

    • Elisabeth Sanchez-Padilla
    •  & Maryline Bonnet
  30. Department of Microbiology, University Hospital La Fe, Valencia, Spain.

    • Ana Gil-Brusola
  31. Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.

    • Matthias Frank
    •  & Francine Ntoumi
  32. Institute Laboratory for Tuberculosis Research (LTR), Biotechnology Center (BTC), University of Yaoundé I, Yaoundé, Cameroon.

    • Veronique N Penlap Beng
  33. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

    • Kathleen Eisenach
  34. Department of Medical Laboratory Technology, Faculty of Medical Technology, Baghdad, Iraq.

    • Issam Alani
  35. Institute of Tropical Medicine and Infectious Diseases (ITROMID), Jomo Kenyatta University of Agriculture and Technology (JKUAT), Nairobi, Kenya.

    • Perpetual Wangui Ndung'u
  36. Department of Pathology, Aga Khan University Hospital (AKUH), Nairobi, Kenya.

    • Gunturu Revathi
  37. Medical Research Council, Fajara, the Gambia.

    • Florian Gehre
  38. Fondation Congolaise pour la Recherche Médicale, Université Marien Gouabi, Brazzaville, Republic of the Congo.

    • Francine Ntoumi
  39. Right to Care and the Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.

    • Lynsey Stewart-Isherwood
  40. National Institute of Medical Research, Mbeya Medical Research Centre (NIMR-MMRC), Mbeya, Tanzania.

    • Nyanda E Ntinginya
  41. Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, and German Centre for Infection Research (DZIF), partner site Munich, Munich, Germany.

    • Andrea Rachow
    •  & Michael Hoelscher
  42. Emerging Bacterial Pathogens Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy.

    • Daniela Maria Cirillo
  43. Riga East University Hospital, Centre of Tuberculosis and Lung Diseases, Riga, Latvia.

    • Girts Skenders
  44. WHO Supranational TB Reference Laboratory, Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.

    • Sven Hoffner
  45. Department of Immunology and Cell Biology, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.

    • Daiva Bakonyte
    •  & Petras Stakenas
  46. Institute for Epidemiology, Schleswig-Holstein University Hospital, Kiel, Germany.

    • Roland Diel
  47. National Tuberculosis Reference Laboratory, Phthysiopneumology Institute, Chisinau, Moldova.

    • Valeriu Crudu
  48. 'Marius Nasta' Pneumophtisiology Institute, Bucharest, Romania.

    • Olga Moldovan
  49. Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    • Sahal Al-Hajoj
  50. Instituto de Medicina Tropical Alexander von Humboldt, Molecular Epidemiology Unit–Tuberculosis, Universidad Peruana Cayetano Heredia, Lima, Peru.

    • Larissa Otero
    •  & Francesca Barletta
  51. Warren Alpert School of Medicine at Brown University, Miriam Hospital, Providence, Rhode Island, USA.

    • E Jane Carter
  52. Moi University School of Medicine, Eldoret, Kenya.

    • E Jane Carter
    •  & Lameck Diero
  53. Université Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR 8204, CIIL, Centre d'Infection et d'Immunité de Lille, Lille, France.

    • Philip Supply
  54. Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.

    • Iñaki Comas
  55. CIBER Epidemiology and Public Health, Madrid, Spain.

    • Iñaki Comas
  56. German Center for Infection Research, Borstel Site, Borstel, Germany.

    • Stefan Niemann

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D.S., D. Brites, L.J., S.N. and S.G. planned the experiments. D.S., L.J., D. Brites, A.T., L.F., L.R., S.B., M. Ballif, Q.L., T.L., Q.G., M.K.-M., M. Bonnet, M.E., R.M., H.M., M.M., G.T.V., J.F., M.G., J.T., F.J., J.L.G., A.A.-P., D.Y.-M., E.W., W.S., M.J., W.H.B., I.B., J.B., M.S., S.E.G.V., P. Suffys, A.K., R.W., L.G.-B., B.M., S.D.L., H.-P.B., B.C.d.J., K.T., E.S.-P., M. Bonnet, A.G.-B., M.F., V.N.P.B., K.E., I.A., P.W.N., G.R., F.G., S. Akter, F.N., L.S.-I., N.E.N., A.R., M.H., D.M.C., G.S., S.H., D. Bakonyte, P. Stakenas, R.D., V.C., O.M., S. Al-Hajoj, L.O., F.B., E.J.C., L.D., P. Supply and I.C. contributed reagents and performed the experiments. D.S., L.J., D. Brites, M.C., S.N. and S.G. analyzed the data. D.S., L.J., D. Brites, S.N. and S.G. wrote the manuscript. All authors critically reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sebastien Gagneux.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14 and Supplementary Tables 1–4, 6 and 8.

Excel files

  1. 1.

    Supplementary Table 5

    Distribution of MTBC lineage 4 clinical isolates per country and per sublineage.

  2. 2.

    Supplementary Table 7

    Whole-genome sequence data accession codes.

  3. 3.

    Supplementary Table 9

    Description of epitopes containing non-singleton nonsynonymous mutations in the four sublineages analyzed.

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DOI

https://doi.org/10.1038/ng.3704

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