Rationale
Tuberculosis remains the world’s leading infectious disease killer, with drug resistance growing. Innate immunity plays a unique role in host defence against Mycobacterium tuberculosis (Mtb), and focus is directed towards the pulmonary macrophage to develop novel host-directed therapies. We have demonstrated the centrality of the bioenergetic response of human macrophages to infection, with glycolytic reprogramming enhancing mycobacterial killing. The role of immunometabolism in the induction of trained immunity has emerged, and will be paramount in developing host-directed vaccines. Discoveries on the impact of macrophage ontogeny upon metabolic and functional responses to antigenic challenge raise questions regarding optimal route and targets for host-directed therapies. Aims and Objectives
Aim 1: To characterise pulmonary macrophage ontogeny in the smoking and non-smoking lung and characterise metabolic and functional differences in these macrophage subpopulations
Aim 2: To define the plasticity of human pulmonary macrophage bioenergetics and investigate the potential of therapeutic agents to manipulate pulmonary macrophage metabolism and improve host immune function against Mtb infection
Aim 3: To establish the role of orally administered meclizine in induction of innate immune memory in pulmonary and circulating macrophages via in vivo human experiments
Research Methodology
Patient samples will be obtained through on-site collaboration with St James’s Hospital, and experimental investigation of metabolic profiles and macrophage function in response to Mtb infection will be conducted and correlated with clinical data collected. Anticipated Outcomes
Applicability of immunometabolism to Mtb infection in the human pulmonary compartment will be defined, and novel clinically-safe, readily-available host-directed therapies identified. These discoveries can serve as new therapeutic options to combat the major global health threat of TB disease
