Projects
Unravelling the Mechanisms of Differential Virulence and Drug Resistance in Bovine TB: M.orygis as a current and emerging threat
Topic: Brucellosis
Summary
Phylogenetically Mycobacterium orygis has been placed as an intermediate between M. tuberculosis and M. bovis. Surprisingly however, neither the pathogenic potential of M. orygis nor the association of its known genomic variation with a drug resistant phenotype have been thoroughly investigated. This has resulted in a gap in the scientific knowledge that is not only essential for understanding the host-pathogen signalling mechanisms used during M. orygis infection, but also critical for effective clinical decision-making for TB diagnosis and therapy.
We hypothesise that the deletion of specific RD regions or select genes in the M. orygis genome, as part of its divergent evolution, has contributed to its altered virulence and pathogenicity evident by its emergence as a significant cause of TB. Additionally, the presence of drug resistance-associated single nucleotide polymorphisms (SNPs) and complementary genetic mutations in the M. orygis genome may contribute to the evident spread of drug resistance in tuberculosis (TB) in both animals and humans.
To bring clarity to the potential zoonotic and/ or anthropozoonotic transmission of M. orygis, it is essential to pick apart how the genomic differences in this tubercle bacillus translates to differential virulence, host-pathogen interaction and the drug resistance when compared to other better studied MTC members. This proposal identifies the increasing incidence of M. orygis infection, and presence of DR and MDR associated mutations in M. orygis clinical isolates across the globe as a significant public health threat and intends to identify and elucidate the molecular mechanism that are driving it. The robust data obtained from the project will help guide policy decisions and contribute to the development of appropriate diagnostic, therapeutic and control strategies for M. orygis infection in both humans and animals.
Objectives & Deliverables
Tuberculosis (TB) is a worldwide problem and has remained the largest global infectious killer known. In addition drug-resistant tuberculosis (DR-TB) continues to rise, limiting the ability to treat the disease, and is part of the research priority to understand and push back against antimicrobial resistance (AMR). The predominant bacteria associated with human TB is Mycobacterium tuberculosis. In the UK over 4000 new cases of TB are recorded annually but in other countries the burden of disease is much higher. The Mycobacterium tuberculosis bacterium is a member of a larger group of related bacteria, the Mycobacterium Tuberculosis Complex (MTC), that preferentially infect other mammals but some of the other MTC members can also cause TB in people. Concern in the UK and elsewhere around bovine TB is partly driven by the risk it poses to human health but in recent epidemiological studies in Asian and South-East Asian countries, a relatively poorly studied member of the MTC, Mycobacterium orygis, has been identified as an increasingly predominant cause of TB in both cattle and wild animals. There is concern that M. orygis is beginning to replace M. bovis as the major cause of zoonotic TB in humans, a major new challenge to the control of TB worldwide. Relatively little is known directly about M. orygis as a pathogen and there is an urgent need to explore its biology to learn more about how it causes disease and what the reasons are for its emergence. In this project we will compare M. tuberculosis, M. bovis and M. orygis to ascertain how the differences among them lead to their success as causes of TB disease in farmed animals and in people. An added concern is that M. orygis already appears somewhat resistant to the drugs currently used to treat TB so a particular dimension of our project will look at the way in which drug resistance works and how this may be circumvented to give effective control.
This scientific project makes use of complementing scientific strengths in India and the UK and represents a critical component in the ongoing drive against TB and AMR in order to develop more effective TB control strategies.
Principle Investigator(s)
Planned Completion date: 01/06/2027
Effort: £440,111
Project Status
Active
Principal Investigator(s)
ISPF
Researcher Organisations
UNIVERSITY OF READING
United Kingdom