Understanding mechanisms of tuberculosis disease severity

By Taane Clark and Jody Phelan.

Summary. Tuberculosis disease, caused by Mycobacterium tuberculosis bacterial bugs, continues to have a profound impact on global health. In 2016 there were an estimated 10.4 million new cases and 1.7 million deaths, making tuberculosis disease the foremost cause of mortality from a single infectious agent. Vital in the fight against the disease is understanding how different bug strain-types affect disease severity. By analysing 16 well characterised strains from around the world, it was possible to identify modifications in the DNA genetic code that are thought to control how genes are “switched” on and off. Identified differences could explain disparities in known virulence and pathogenicity, and ultimately lead to improved management and control of the infectious disease.

Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally

A collaborative project led by scientists at LSHTM has advanced our understanding of the genetic regulation of Mycobacterium tuberculosis complex bacteria that cause tuberculosis disease in humans. DNA methylation is an ‘epigenetic’ modification of the bacterial genome that controls how genes are turned on and off, including those regulating crucial cellular processes, such as transcription and chromosome stability. The M. tuberculosis bacterial methylome, all of the methylation, is poorly understood but likely has roles in virulence, survival in low oxygen environments, and the emergence of drug resistance. By applying the emerging technology, PacBio sequencing, the researchers accurately characterised the genome-wide sequences and the methylome across 16 strains representing 6 major lineages within the Mycobacterium tuberculosis complex. The analysis published in Scientific Reports (Phelan et al, 2018) revealed that some strains have an absence of methylation, which was related to ‘loss of function’ mutations in the genes which control the methylation process. When comparing these findings to other global samples, the researchers found that those mutations were specific to certain lineages of M. tuberculosis. Insights into lineage-specific methylomes such as these will untangle the impacts of the epigenome, and identify currently unknown biological mechanisms, which could be used to develop new measures for Mycobacterium control.



Phelan J, de Sessions PF, Tientcheu L, Perdigao J, Machado D, Hasan R, Hasan Z, Bergval IL, Anthony R, McNerney R, Antonio M, Portugal I, Viveiros M, Campino S, Hibberd ML, Clark TG. Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally. Sci Rep. 2018 Jan 9;8(1):160. doi: 10.1038/s41598-017-18188-y.