Towards host-directed therapies to overcome immune impairment in cigarette smokers during mycobacterial infection

Tuberculosis (TB) is a bacterial infection which causes approximately 1.5 million deaths worldwide each year and it is estimated that one third of the worlds'population is latently infected with TB. In this proposal we aim to investigate the role of alveolar acrophages in the immune response to TB infection. Alveolar macrophages are specialized cells that fight bacterial infections in the lung. TB bacilli infect alveolar macrophages and inhibit their antibacterial activity in order to avoid being eliminated by the immune system. Cigarette smokers (and people in developing countries who use biomass fuels to cook food indoors) are more susceptible to TB than non-smokers. One reason for this may be that their alveolar macrophages are less efficient at fighting infections. We hypothesise that smokers'alveolar macrophages respond differently to those of non-smokers when they are infected with TB. microRNAs are recently discovered DNA-like molecules that can block the expression of genes involved in regulating the response of immune cells to infection. Alveolar macrophages will be obtained from smokers and non-smokers who consent to take part in the study, by washing out a lobe of the lung during bronchoscopy. The alveolar macrophages will be cultured in the lab and infected with TB. We will obtain a profile of all of the microRNAs and genes that are expressed during TB infection using RNA sequencing and identify those that are differentially expressed in smokers'macrophages. A better understanding of the role
that microRNAs play in TB may aid in the design of more effective therapies and vaccines. In Ireland the majority of TB patients smoke, and this research might lead to bespoke therapy for this uniquely susceptible group.

Award Date
01 July 2016
Award Value
€100,000
Principal Investigator
Professor Joseph Keane
Host Institution
Trinity College Dublin
Scheme
MRCG-HRB Joint Funding Scheme