Bovine and human tuberculosis: probing the genetic, molecular and structural basis of lipid-mediated pathogenesis mechanisms

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

The human pathogen Mycobacterium tuberculosis and bovine pathogen Mycobacterium bovis have complex cell walls, rich in unique mycolic acid lipids that play an important role in virulence, adhesion, immunomodulation and biofilm formation. Using an interdisciplinary approach, the role of transcriptional regulation in the mycolic acid biosynthesis pathway will be explored for its impact on lipid mediated pathogenesis mechanisms during initial infection and persistence within the host.

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 31/03/2024
1790828 Studentship BB/M01116X/1 03/10/2016 25/01/2021 Charlotte Cooper
 
Description Mycolic acids are the unique and essential major fatty acid components of the cell wall of M. tuberculosis, the causative agent of tuberculosis. Biosynthesis of mycolic acids is a key target for current drugs and future drug development and so an understanding of the synthesis pathway and regulation of this in response to infection is important with the cell wall being a key virulence factor for the bacterium.

We have identified a transcriptional repressor; mycolic acid desaturase regulator (MadR) that regulates the genes responsible for essential desaturation events in the biosynthesis of mycolic acids (desA1 and desA2). Desaturation of mycolic acids is a necessary precursor for virulence modificatons such as cycloproponation that if knocked out result in complete attenuation of virulence. We have established with our existing collaborators at the Institute of Systems Biology, Seattle by using the path-seq method; a way of measuring gene expression during macrophage infection of M. tuberculosis, that desA1 and desA2 are upregulated in the early stages of infection and downregulated later in infection and persistence corresponding with the theory that mycolic acids are remodelled throughout the infection cycle. MadR therefore may be a key regulator of cell wall mycolic acid remodelling through regulation of expression of desA1 and desA2 in response to different stages of infection. When we overexpress MadR we get a loss of viability and deletion of MadR results in a dramatic difference in the cell wall mycolic acids resulting in increased cell wall permeability and susceptibility to key anti-TB drugs. In addition, a key finding is that MadR responds to cell surface disruption to relieve regulation of desA1 and desA2 expression leading to remodelling of the cell wall mycolic acids. The ligand to which MadR responds and the mechanism of regulation was elucidated and offers MadR as a key regulatory element of mycolic acid synthesis during normal growth and intracellular conditions. Cell surface disruption occurs during macrophage infection and though little is known about the exact method of disruption, MadR responding to this gives insight into environmental cues for the regulation of mycolic acid remodelling during infection. MadR is a transcriptional repressor and so repression of desA1 and desA2 later in infection and persistence provides insight into the downregulation of mycolic acid synthesis in this difficult to target stage of the infection cycle.
Exploitation Route These outcomes give insight into the transcriptional regulation of mycolic acid synthesis during active infection in response to macrophage associated stress factors and during persistence. This is a shared mechanism between human and bovine tuberculosis and so spans both healthcare and agriculture. The cell wall is a key target for drug development. The dramatic impact of disruption of MadR regulation on one hand viability and on the other with increased susceptibility to current anti-TB drugs, and the key role it may play during both active and persistent infection offers MadR as a good target for drug development for different stages of infection.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description World TB day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As part of the lab group of Liz Fullam at the University of Warwick we organised two events in 2017 and 2018 to help promote the important public health messages about tuberculosis (TB). We engaged with the public to help raise awareness of the disease, symptoms and treatments, as well as spreading the message of what we are trying to do to combat the deadly disease. We ran a stand at a local shopping centre in 2017 and at a museum and art gallery in 2018 which reached in both cases at least 150 people (number of flyers handed out).
Many of the older generation had their own stories of parents or relatives contracting TB and were happy that we were carrying on research as they knew the toll it takes first hand, and most of those we spoke to thought TB was a disease of the past and were shocked to find that it is the leading killer of any infectious disease and cases are rising in the UK. We ran colouring competitions and a quiz as well as giving out balloons and stickers to engage a younger audience, we received a number of responses to the competitions and gave away GIANTmicrobes Tuberculosis toys to the winners which were generously donated by the company. We also engaged with the local TB treatment nurses who played a role in collaborating with our events.
Year(s) Of Engagement Activity 2017,2018
URL https://warwick.ac.uk/newsandevents/pressreleases/university_of_warwick_brings_tb_awareness_to_coven...