There have been exciting advances in pulmonary research and host defense recently. Specifically, we have demonstrated a crucial role from metabolic reprogramming in driving anti-infectious pathways in the lung. We have used new technologies to characterize pulmonary immune cells ontogeny and shown how macrophages of different sources contribute to host defense and susceptibility. Whereas these new research approaches have been optimized in our lab, we now propose to exploit them to address the important question of persisting infection in patients with cystic fibrosis. This application will address macrophage phenotypes in cystic fibrosis lungs that interfere with the host response – such as impaired macrophage migration, and inadequate immunometabolic switching after infection. By studying the influence of CFTR on this phenotype, it is hoped to uncover not just pathways of importance but also interventions of promise (CFTR ‘correctors’) that might support host defense. This will develop a new paradigm of pulmonary immunity that can lead, in turn, to host directed therapies – that will address the important CF clinical problems of persisting Mycobacterium abscessus and pseudomonas infection.
