Mycobacterium tuberculosis (Mtb) infection causes approximately 1.5 million deaths per year. Cigarette smoking is one of the single largest risk factors driving the global epidemic with a relative risk of 1.5 for progression from latent tuberculosis infection (LTBI) to active disease. Alveolar macrophages (AMs) provide the first line of defence against invading pathogens but smoker’s alveolar macrophages exhibit multiple defects in host-protective macrophage responses including altered microRNA (miRs) expression – which may render them uniquely susceptible to Mtb infection. Our overall goal is to expand the current understanding of miRs regulation, and consequently target mRNAs, in smokers’ macrophages following exposure to Mtb, to identify novel targets for host-directed therapies. Accordingly our specific aims are:
1. Perform global profiling of changes in microRNA expression induced in response to phagocytosis of Mtb in order to identify microRNAs which act as immunomodulators during Mtb infection in non-smokers and smokers’ alveolar macrophages using next generation sequencing.
2. Characterise the response of smokers’ and non-smokers alveolar macrophages to miRs that stimulate autophagy and promote anti-microbial activity using miR and target site inhibitors, and gain-of-function experiments.
The use of host directed therapies consisting of targeting host anti-microbial pathways regulated by miRs is an emerging concept in TB treatment. A better understanding of the molecular mechanisms responsible for the inadequate immune response of smokers’ macrophages to Mtb infection will be crucial in determining which host-directed therapies will benefit this cohort of patients.
