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

Oberkircher, L. M.; Scheiding, V. M.; Rafeld, H. L.; Hanssen, E.; Hansen, J. N.; Fleischmann, M. J.; Kessler, N. M.; Pitsch, D.; Wachten, D.; Kastenmueller, W.; Brown, A. S.; Hartland, E.; van Driel, I. R.; Ng, G. Z.; Garbi, N.

doi:10.1101/2024.01.31.578217

bioRxiv · 10.1101/2024.01.31.578217

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

Oberkircher, L. M.·Scheiding, V. M.·Rafeld, H. L.·Hanssen, E.·Hansen, J. N.·Fleischmann, M. J.·Kessler, N. M.·Pitsch, D.·Wachten, D.·Kastenmueller, W.·Brown, A. S.·Hartland, E.·van Driel, I. R.·Ng, G. Z.·Garbi, N.

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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 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 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-{gamma} 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 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/578217v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@107c421org.highwire.dtl.DTLVardef@dd76f5org.highwire.dtl.DTLVardef@1acf746org.highwire.dtl.DTLVardef@9e2c17_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAM serve as a replicative niche and promote L. longbeachae infection. C_LIO_LIInfiltrating neutrophils and MC kill L. longbeachae. C_LIO_LIIFN-{gamma} from IL-18R+ NK and T cells stimulates ROS and bacterial clearance. C_LI

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Oberkircher, L. M., Scheiding, V. M., Rafeld, H. L., Hanssen, E., Hansen, J. N., Fleischmann, M. J., Kessler, N. M., Pitsch, D., Wachten, D., Kastenmueller, W., Brown, A. S., Hartland, E., van Driel, I. R., Ng, G. Z., Garbi, N.. 2024-02-01. Opposing roles of resident and infiltrating immune cells in the defence against Legionella longbeachae via IL-18R/IFN-γ/ROS axis. https://doi.org/10.1101/2024.01.31.578217

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