Cigarette smoke depletes alveolar macrophages and delays clearance of Legionella pneumophila

Legionella pneumophila is the main aetiological agent of Legionnaires' Disease, a severe bacterial pneumonia. L. pneumophila is initially engulfed by alveolar macrophages (AM) and subverts normal cellular functions to establish a replicative vacuole. Cigarette smokers are particularly susceptible to developing Legionnaires' Disease and other pulmonary infections. However, little is known about the cellular mechanisms underlying this susceptibility. To investigate this, the authors used a mouse model of acute cigarette smoke exposure to examine the immune response to cigarette smoke and subsequent L. pneumophila infection. Contrary to previous reports, the study shows that exposure to cigarette smoke causes a significant depletion of AM using enzymatic digestion to extract cells or image intact lung lobes by light-sheet microscopy. Further, treatment of mice deficient in specific types of cell death with smoke suggests that NLRP3-driven pyroptosis contributes to AM's smoke-induced death. In summary, the results showed that cigarette smoke depleted AM from the lung and likely contributed to more severe Legionnaires' Disease. Further, the role of AM in L. pneumophila infection is more nuanced than simply providing a replicative niche, and the studies suggest they play a major role in bacterial clearance.