The function and regulation of tissue resident alveolar macrophages turnover by host and environmental factors during homeostasis and in infections

With 3 million deaths per year, lower respiratory tract infections are the leading infectious cause of death and the fifth-leading cause of death overall. Therefore, it is extremely important to understand how our respiratory immune system works and potentially discover ways to therapeutically improve lung capacity. The majority of immune cells living in the alveoli are resident alveolar macrophages (resident AMs). They constantly "crawl" in the alveoli and clear bacteria we breathe in to keep our lungs clean. It is now well known that there is a gradual replacement of AMs by monocytes that then assume the role of AMs (replacement AMs). I am interested in understanding if there is an advantage to AM turnover, or whether this is simply a negative side effect of ageing. A further question is whether this turnover is expedited by factors including seasonal flu, COVID-19 or environmental factors including pollutants, silicosis and other contaminants. We now have a mouse in which the replacement AMs are fluorescent red while the resident AMs are blue. This allows us to systematically examine how these two different AM populations behave (e.g. crawling, bacterial clearance) inside the lungs of living mice. To explore the environmental factors on 1): resident AM turnover; and 2) the behaviour of AMs, we will examine mice in a completely germ-free environment that have no microbes at all and mice that are co-housed with wild mice so they have a very robust microbiome with numerous infections. Finally, BCG vaccine induces "trained immunity" which makes immune cells respond more robustly to all infections and we will test if AMs can be trained to enhance defenses against lung infections caused by bacteria, flu and SARS-CoV-2. The outcome of this study will provide unprecedented insights into how host and environmental factors imprint AM function and how the underlying mechanism(s) may be used to guide the development of novel therapeutic strategies for lung infections.