Opposing roles of resident and infiltrating immune cells in the defence againstLegionella longbeachaevia IL-18R/IFN-γ/ROS axis

Abstract

AbstractThe immune response againstLegionella longbeachae, a causative agent of the often-fatal Legionnaires’ pneumonia, is poorly understood. Here we investigated the specific roles of tissue-resident alveolar macrophages (AM) and infiltrating phagocytes during infection with this pathogen. AM were the predominant cell type that phagocytosed bacteria o day after infection. Three and five days after infection, AM numbers were greatly reduced while there was an influx of neutrophils and later monocyte-derived cells (MC) into lung tissue. AM carried greater numbers of viableL. longbeachaethan neutrophils and MC, which correlated with a higher capacity ofL. longbeachaeto translocate bacterial effector proteins required for bacterial replication into the AM cytosol. Cell ablation experiments demonstrated that AM promoted infection whereas neutrophils and MC were required for efficient bacterial clearance. IL-18 was important for IFN-γ production by IL-18R+NK cells and T cells which, in turn, stimulated ROS-mediated bactericidal activity in neutrophils resulting in restriction ofL. longbeachaeinfection. Ciliated epithelial cells also expressed IL-18R but did not play a role in IL-18-mediatedL. longbeachaeclearance. Our results have identified opposing innate functions of tissue-resident and infiltrating immune cells duringL. longbeachaeinfection that may be manipulated to improve protective responses.HighlightsAM serve as a replicative niche and promoteL. longbeachaeinfection.Infiltrating neutrophils and MC killL. longbeachae.IFN-γ from IL-18R+NK and T cells stimulates ROS and bacterial clearance.