Understanding the role of the respiratory tract microbiota in immunity to bacterial infection in COPD (360G-Wellcome-215275_Z_19_Z)

Understanding how the recently identified airway microbiota interacts with the unique immune system of the lung to protect against infection in health and how these interactions are disturbed in COPD is a crucial question both clinically and biologically. Since cause/effect cannot be inferred from human studies, I will utilise microbiota manipulation in novel murine models to understand the function of the airway microbiota in shaping lung-specific immunity and defining infection susceptibility. I hypothesise that commensals perturbed within the COPD airway microbiota can influence infection susceptibility through modulation of the anti-microbial peptide cathelicidin. Aim 1 will build on my previously developed novel murine model of selective respiratory tract microbiota depletion to understand how the airway microbiota affects immunity to bacterial infection. Aim 2 will utilise gain/loss of function experiments to interrogate the role of cathelicidin in microbiota-induced protection against infection. Aim 3 will examine whether commensals associated with disease/health that are perturbed in COPD patients who frequently exacerbate can modulate lung-specific immunity and infection susceptibility. Key goals will be:(1) Development of robust murine models of microbiota manipulation. (2) Generation of preliminary data to provide feasibility for Fellowship applications. (3) Development of new skills in bacteriology/molecular microbiology to facilitate development of independence.