Impact of studying TB metabolism
Non-tuberculous Lung Disease (NTM) and Tuberculosis (TB) are lung diseases caused by two bacterial species, Mycobacterium avium and Mycobacterium tuberculosis, respectively. While the morbidity and mortality attributed to TB is well described and is considered to be a dire global health issue, the public health significance of NTM is relatively under-appreciated. NTM represents an increasingly severe health problem in the US and other countries where clinical presentation, diagnosis and treatment is often confounded by the overlapping symptoms of disease and the genetic similarity of M. avium and M. tuberculosis. Despite these similarities, the consequence of misdiagnosis and inappropriate treatment can have fatal consequences for the patient.
The interplay between a mycobacterial pathogen and its host is characterised by a complex, dynamic escalation of responses in which both participants co-adapt to the best efforts of the other. In most cases, the infecting bacterial organisms succumb to the host immune response; sometimes, however, the bacteria are able to establish chronic infections leading to significant lung disease. Importantly, both M. avium and M. tuberculosis elicit a similar host immune response. One physiological hallmark of the immune response to mycobacterial lung disease is the development of the granulomatous lesion, whose function is to contain the infection, to isolate immune-mediated damage from the surrounding tissue, and to create a biochemically hostile environment that restricts the survival and replication of the bacilli.
Despite our progress in understanding the vertebrate immune response, we have only a limited understanding of how mycobacteria adapt to immune-mediated physiological stress; in particular, we know little about how they respond to the environment within the granulomatous lesion. The long-term focus of my research program is to identify the strategies responsible for the capacity of M. avium and M. tuberculosis to survive and grow in the hostile environment found within this lesion. We approach this research problem from the perspective that bacterial survival and growth is mediated by mechanisms through which the bacilli sense their environment, the manner in which these sensory signals are integrated, and the resulting genetic program that provides the bacteria with appropriate tools necessary to modify, escape or evade the host response.
We have so far identified specific genetic compensatory differences between M. avium and M. tuberculosis in their response to oxygen limitation, a well-described consequence of the granulomatous lesion, as well as described their response to nitric oxide exposure, a toxic antibacterial metabolite generated by the activated macrophage. We are currently investigating the regulatory mechanisms associated with these compensatory differences.
Understanding how these bacilli adapt to and shape their environment will identify essential and novel pathways that will produce new drug development leads and thereby improve treatment strategies for the control of both non-tuberculous mycobacterial lung disease and tuberculosis.
The specific goal of Dr. John Pearl’s research program is to advance our understanding of mycobacterial physiology in order to identify specific metabolic states in which bacteria might be (1) rendered most susceptible to existing chemotherapy, perhaps through drug-based interference of its perception of its environment or through biasing the integration of the multiple sensory signals; and (2) to identify the hallmarks of a host immune response that induce a susceptible bacterial metabolic state in order to development an improved and highly targeted anti-TB or anti-NTM vaccine.
Metabolic regulation in Mycobacterium tuberculosis
Reversible protein phosphorylation on serine and threonine is a ubiquitous mechanism of signal transduction in bacteria. Our research focuses on how bacteria sense and respond to the environment, with particular focus on the pathogen Mycobacterium tuberculosis, and related bacteria used in bioindustry.
One of the most common and conserved bacterial kinases is protein kinase G (PknG) and we have shown how the PknG signalling pathway allows M. tuberculosis and other bacteria to sense abundant amino acids and adjust their carbon central metabolism to make use of the available nutrients.
The stimuli of serine threonine kinase activation and the downstream effects of kinase activation are outstanding questions in bacterial signalling. As a result of our work, PknG is one of only a handful of bacterial S/T kinases for which the activation stimuli are known, and the only bacterial FHA-mediated signalling pathway with a complete molecular description (FHA=is a phospho-threonine recognition domain found in all domains of life).
Structure and Tuberculosis
Collaboratively, the LeMID network are working to validate anti-TB drug targets and for structure based drug discovery (Russell Wallis), to study protein phosphorylation at the level of the phosphoproteome and in regulation of bacterial cell growth (Prof. Galina Mukamolova), and to study the function of these signalling pathways in infection models (Leicester TB Research Group).