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, Valérie Barbe, Claudine Médigue, Laurence Ma, Christiane Bouchier, Arianna Tavanti, Gerald Larrouy‐Maumus, Roland Brosch
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.