Journal Article

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

Spadoni, Dalila, Brosch, Roland, Hardy, David, Tavanti, Arianna, Di Luca, Mariagrazia, Orgeur, Mickael, Sayes, Fadel, Medigue, Claudine, Larrouy-Maumus, Gerald, Zoppo, Marina, Ma, Laurence, Bouchier, Christiane, Mangenot, Sophie, Pawlik, Alexandre, Khanna, Varun, Frigui, Wafa, Bottai, Daria, Barbe, Valerie

2020

Overview

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. Mycobacterium tuberculosis (Mtb) modern strains emerged from a common progenitor after the loss of Mtb-specific deletion 1 region (TbD1). Here, the authors show that deletion of TbD1 correlates with enhanced Mtb virulence in animal models, mirroring the development of hypoxic granulomas in human disease progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/44 / 631/326/421 / 64 / 64/60 / 692/699/255 / Animal models / Animals / Bacteriology / Biochemistry / Biochemistry, Molecular Biology / Biodiversity / Cell Behavior / Cellular Biology / Clinical isolates / Clonal deletion / Deletion / Epidemics / Evolution, Molecular / Guinea Pigs / Humanities and Social Sciences / Humans / Hypoxia / Life Sciences / Mice / Mice, Inbred C3H / Microbiology and Parasitology / multidisciplinary / Mycobacterium tuberculosis / Mycobacterium tuberculosis - classification / Mycobacterium tuberculosis - genetics / Mycobacterium tuberculosis - pathogenicity / Oxidation resistance / Oxidative stress / Phylogeny / Populations and Evolution / Science / Science (multidisciplinary) / Sequence Deletion / Tuberculosis / Tuberculosis - microbiology / Virulence