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

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, Claudine Medigue, Laurence Ma, Christiane Bouchier, Arianna Tavanti, Gerald Larrouy-Maumus and Roland Brosch ()
Additional contact information
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14508-5

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