Opposing roles of resident and infiltrating immune cells in the defence against Legionella longbeachae via IL-18R/IFN-γ/ROS axis in mice

Lara M Oberkircher; Victoria M Scheiding; H Linda Rafeld; Eric Hanssen; Jan N Hansen; Markus J Fleischmann; Nina Kessler; David Pitsch; Dagmar Wachten; Wolfgang Kastenmüller; Andrew S Brown; Elizabeth L Hartland; Ian R van Driel; Garrett Z Ng; Natalio Garbi

doi:10.1016/j.mucimm.2024.05.001

Opposing roles of resident and infiltrating immune cells in the defence against Legionella longbeachae via IL-18R/IFN-γ/ROS axis in mice

Mucosal Immunol. 2024 May 13:S1933-0219(24)00042-4. doi: 10.1016/j.mucimm.2024.05.001. Online ahead of print.

Authors

Affiliations

¹ Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton 3168, Australia; Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.
² Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany; Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia.
³ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton 3168, Australia; Life & Medical-Sciences Institute, University of Bonn, Germany.
⁴ Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia; Ian Holmes Imaging Centre, University of Melbourne, Victoria, Australia.
⁵ Institute of Innate Immunity, Faculty of Medicine, University of Bonn, Germany; Current address: Department of Bioengineering, Stanford University, USA.
⁶ Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany.
⁷ Institute of Innate Immunity, Faculty of Medicine, University of Bonn, Germany.
⁸ Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, Germany.
⁹ Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia; Current address: LEO Foundation Skin Immunology Research Centre, Department of Immunology and Microbiology, University of Copenhagen, Denmark.
¹⁰ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton 3168, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Australia.
¹¹ Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia.
¹² Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton 3168, Australia; Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Australia.
¹³ Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany. Electronic address: ngarbi@uni-bonn.de.

PMID: 38750967
DOI: 10.1016/j.mucimm.2024.05.001

Abstract

The immune response against Legionella 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 internalized bacteria one 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 viable L.longbeachae than neutrophils and MC, which correlated with a higher capacity of L.longbeachae to 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 of L.longbeachae infection. Ciliated bronchiolar epithelial cells also expressed IL-18R but did not play a role in IL-18-mediated L.longbeachae clearance. Our results have identified opposing innate functions of tissue-resident and infiltrating immune cells during L.longbeachae infection that may be manipulated to improve protective responses.

Keywords: IFN-γ; Interleukin 18; Legionella; ROS; monocyte-derived macrophages; monocytes; neutrophils; tissue-resident macrophages.