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Hailu et al_Microbial Genomics_2023.pdf (1.67 MB)

Lack of methoxy-mycolates characterizes the geographically restricted lineage 7 of Mycobacterium tuberculosis complex

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posted on 2023-06-10, 07:08 authored by Elena Hailu, Daire Cantillon, Carlos Madrazo, Graham Rose, Paul R Wheeler, Paul Golby, Bethlehem Adnew, Sebastien Gagneux, Abraham Aseffa, Stephen V Gordon, Iñaki Comas, Douglas B Young, Simon WaddellSimon Waddell, Gerald Larrouy-Maumus, Stefan Berg
Lineage 7 (L7) emerged in the phylogeny of the Mycobacterium tuberculosis complex (MTBC) subsequent to the branching of 'ancient' lineage 1 and prior to the Eurasian dispersal of 'modern' lineages 2, 3 and 4. In contrast to the major MTBC lineages, the current epidemiology suggests that prevalence of L7 is highly confined to the Ethiopian population, or when identified outside of Ethiopia, it has mainly been in patients of Ethiopian origin. To search for microbiological factors that may contribute to its restricted distribution, we compared the genome of L7 to the genomes of globally dispersed MTBC lineages. The frequency of predicted functional mutations in L7 was similar to that documented in other lineages. These include mutations characteristic of modern lineages - such as constitutive expression of nitrate reductase - as well as mutations in the VirS locus that are commonly found in ancient lineages. We also identified and characterized multiple lineage-specific mutations in L7 in biosynthesis pathways of cell wall lipids, including confirmed deficiency of methoxy-mycolic acids due to a stop-gain mutation in the mmaA3 gene that encodes a methoxy-mycolic acid synthase. We show that the abolished biosynthesis of methoxy-mycolates of L7 alters the cell structure and colony morphology on selected growth media and impacts biofilm formation. The loss of these mycolic acid moieties may change the host-pathogen dynamic for L7 isolates, explaining the limited geographical distribution of L7 and contributing to further understanding the spread of MTBC lineages across the globe.

History

Publication status

  • Published

File Version

  • Published version

Journal

Microb Genom

ISSN

2057-5858

Publisher

Microbiology Society

Issue

5

Volume

9

Page range

1-16

Event location

England

Department affiliated with

  • Global Health and Infection Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2023-05-24

First Open Access (FOA) Date

2023-05-24

First Compliant Deposit (FCD) Date

2023-05-23

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