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TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages

Author

Listed:
  • Daria Bottai

    (University of Pisa)

  • Wafa Frigui

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics)

  • Fadel Sayes

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics)

  • Mariagrazia Di Luca

    (University of Pisa)

  • Dalila Spadoni

    (University of Pisa)

  • Alexandre Pawlik

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics)

  • Marina Zoppo

    (University of Pisa)

  • Mickael Orgeur

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics)

  • Varun Khanna

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics
    Hub Bioinformatique et Biostatistique, Institut Pasteur - C3BI)

  • David Hardy

    (Institut Pasteur, Experimental Neuropathology Unit)

  • Sophie Mangenot

    (Université Evry, Université Paris-Saclay)

  • Valerie Barbe

    (Université Evry, Université Paris-Saclay)

  • Claudine Medigue

    (Université Paris-Saclay)

  • Laurence Ma

    (Institut Pasteur, Plate-forme génomique, Pasteur Genopole Ile de France)

  • Christiane Bouchier

    (Institut Pasteur, Plate-forme génomique, Pasteur Genopole Ile de France)

  • Arianna Tavanti

    (University of Pisa)

  • Gerald Larrouy-Maumus

    (Imperial College London)

  • Roland Brosch

    (Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics)

Abstract

Mycobacterium tuberculosis (Mtb) strains are classified into different phylogenetic lineages (L), three of which (L2/L3/L4) emerged from a common progenitor after the loss of the MmpS6/MmpL6-encoding Mtb-specific deletion 1 region (TbD1). These TbD1-deleted “modern” lineages are responsible for globally-spread tuberculosis epidemics, whereas TbD1-intact “ancestral” lineages tend to be restricted to specific geographical areas, such as South India and South East Asia (L1) or East Africa (L7). By constructing and characterizing a panel of recombinant TbD1-knock-in and knock-out strains and comparison with clinical isolates, here we show that deletion of TbD1 confers to Mtb a significant increase in resistance to oxidative stress and hypoxia, which correlates with enhanced virulence in selected cellular, guinea pig and C3HeB/FeJ mouse infection models, the latter two mirroring in part the development of hypoxic granulomas in human disease progression. Our results suggest that loss of TbD1 at the origin of the L2/L3/L4 Mtb lineages was a key driver for their global epidemic spread and outstanding evolutionary success.

Suggested Citation

  • Daria Bottai & Wafa Frigui & Fadel Sayes & Mariagrazia Di Luca & Dalila Spadoni & Alexandre Pawlik & Marina Zoppo & Mickael Orgeur & Varun Khanna & David Hardy & Sophie Mangenot & Valerie Barbe & Clau, 2020. "TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14508-5
    DOI: 10.1038/s41467-020-14508-5
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    Cited by:

    1. Yuzhe Weng & Dawn Shepherd & Yi Liu & Nitya Krishnan & Brian D. Robertson & Nick Platt & Gerald Larrouy-Maumus & Frances M. Platt, 2022. "Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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