Neutrophil and Alveolar Macrophage-Mediated Innate Immune Control of Legionella pneumophila Lung Infection via TNF and ROS.
Legionella pneumophila is a facultative intracellular bacterium that lives in aquatic environments where it parasitizes amoeba. However, upon inhalation of contaminated aerosols it can infect and replicate in human alveolar macrophages, which can result in Legionnaires' disease, a severe form of pneumonia. Upon experimental airway infection of mice, L. pneumophila is rapidly controlled by innate immune mechanisms. Here we identified, on a cell-type specific level, the key innate effector functions responsible for rapid control of infection. In addition to the well-characterized NLRC4-NAIP5 flagellin recognition pathway, tumor necrosis factor (TNF) and reactive oxygen species (ROS) are also essential for effective innate immune control of L. pneumophila. While ROS are essential for the bactericidal activity of neutrophils, alveolar macrophages (AM) rely on neutrophil and monocyte-derived TNF signaling via TNFR1 to restrict bacterial replication. This TNF-mediated antibacterial mechanism depends on the acidification of lysosomes and their fusion with L. pneumophila containing vacuoles (LCVs), as well as caspases with a minor contribution from cysteine-type cathepsins or calpains, and is independent of NLRC4, caspase-1, caspase-11 and NOX2. This study highlights the differential utilization of innate effector pathways to curtail intracellular bacterial replication in specific host cells upon L. pneumophila airway infection.
Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
Pascal
P
Ziltener
Institute for Molecular Medicine and Cell Research and Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Thomas
T
Reinheckel
Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
Annette
A
Oxenius
D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D016952:Legionella pneumophila / Q000276:immunology; D007877:Legionnaires' Disease / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha