We are studying the genetic and molecular basis of virulence in members of the Mycobacterium tuberculosis complex.

Cow looking at researcher using laptop

Challenge

The Mycobacterium tuberculosis complex is comprised of a group of closely related bacteria with distinct host preferences. Species such as Mycobacterium bovis causes TB in animals, but has a wide host range. Species such as Mycobacterium tuberculosis and Mycobacterium africanum primarily cause TB in humans. Human TB is one of the top 10 causes of death from a single infectious agent and causes approximately 1.5 million deaths annually. The costs of control programmes of M. bovis infection in domestic livestock are prohibitively expensive and in LMIC M. bovis can represent a zoonotic risk. Unlike many other bacterial pathogens, members of the MTBC are highly genetically similar (>99% similar) and so we are trying to understand the genetic basis of host adaptation and virulence in both M. bovis and M. tuberculosis using a One Health approach. Despite the availability of many genome sequences we still do not understand the roles of many genes in virulence (e.g. virulence factors).

Cow looking at researcher using laptop

Solution

We are using whole genome approaches (Transposon insertion sequencing) to identify the gene required for survival in vivo. Additionally, we are using CRISPRi mediated gene silencing to investigate host pathogen interactions for selected gene targets. We are also utilising CRISPRi to determine target vulnerabilities for therapeutic agents for human tuberculosis. Through a better understanding of host:pathogen interactions in the two species we hope to generate novel therapeutics.

Partners

The work has been funded by several sources including; The Royal Society, The International Veterinary Vaccinology Network, the BBSRC and Defra

Publications/Presentations

Title Publication Year
Challenges in Defining the Functional, Non-Coding, Expressed Genome of Pathogenic Mol Microbiol 2021
Probing Differences in Gene Essentiality Between the Human and Animal Adapted Lineages of the Mycobacterium tuberculosis Complex Using TnSeq Frontiers in Veterinary Science 2021
Molecular basis for DarT ADP-ribosylation of a DNA base Nature 2021
Re-sensitization of Mycobacterium smegmatis to Rifampicin Using CRISPR Interference Demonstrates Its Utility for the Study of Non-essential Drug Resistance Traits Front Microbiol 2021
Zoonotic tuberculosis — a call for an open One Health debate Lancet Infect Dis 2020
A Novel TetR-like transcriptional regulator is induced in acid-nitrosative stress and controls expression of an efflux pump in mycobacteria Front Microbiol 2017
Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections Br J Pharmacol 2017
The structure of the transcriptional repressor kstr in complex with coa thioester cholesterol metabolites sheds light on the regulation of cholesterol catabolism in mycobacterium tuberculosis J Biol Chem 2016
Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions BMC Genomics 2015
Characterisation of a putative AraC transcriptional regulator from Mycobacterium smegmatis Tuberculosis 2014
Purification, crystallization and preliminary X-ray crystallographic studies of KstR2 (ketosteroid regulatory protein) from Mycobacterium tuberculosis Acta Crystallogr Sect FStructural Biol Commun 2014
bkaR is a TetR-type repressor that controls an operon associated with branched-chain keto-acid metabolism in Mycobacteria FEMS Microbiol Lett 2013
Cholesterol metabolism in Mycobacterium smegmatis Environ Microbiol Rep 2012
Rapid construction of mycobacterial mutagenesis vectors using ligation-independent cloning J Microbiol Methods 2010
Cholesterol utilization in mycobacteria is controlled by two TetR-type transcriptional regulators: kstR and kstR2 Microbiology 2010

 

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