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 (AMs) and infiltrating phagocytes during infection with this pathogen. AMs were the predominant cell type that internalized bacteria 1 day after infection. A total of 3 and 5 days after infection, AM numbers were greatly reduced, whereas there was an influx of neutrophils and, later, monocyte-derived cells (MCs) into lung tissue. AMs carried greater numbers of viable L. longbeachae than neutrophils and MCs, 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. Interleukin (IL)-18 was important for interferon-γ production by IL-18R+ natural killer cells and T cells, which, in turn, stimulated reactive oxygen species–mediated bactericidal activity in neutrophils, resulting in the 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Mucosal Immunology |
| Vol/bind | 17 |
| Udgave nummer | 5 |
| Sider (fra-til) | 777-792 |
| Antal sider | 16 |
| ISSN | 1933-0219 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:Work in the laboratory of N. Garbi is supported by DFG grants IRTG2168 \u2013 project-ID 272482170; SFBTRR237 \u2013 project-ID 369799452; SFB1454 \u2013 project-ID 432325352; Excellence Strategy EXC2151 \u2013 project-ID 390873048. Work in the laboratories of I. R. van Driel and E. L. Hartland was supported by the Victorian Government\u2019s Operational Infrastructure Support Program and awards from the University of Melbourne and the Australian National Health and Medical Research Council (NHMRC), including APP1175976. M.F. was supported by a Graduate Research Scholarship from the University of Melbourne. Work in the laboratory of D. Wachten is supported by the DFG: SFB 1454 \u2013 Project-ID 432325352, TRR333/1 \u2013 Project-ID 450149205, FOR5547\u2013- Project-ID 503306912, WA 3382/8-1 \u2013 Project-ID 513767027, under Germany\u2019s Excellence Strategy \u2013 EXC2151 \u2013 Project-ID 390873048, and the Else Kr\u00F6ner Fresenius Foundation (2021.EKFSE.53). JNH was supported with a PhD fellowship from the Boehringer Ingelheim Fonds. We thank Dr. Luis Alvarez (Caesar, Bonn) for supporting high-speed imaging equipment for imaging the ciliary beating in lung slices, in particular, the PCO Dimax high-speed camera.
Funding Information:
The authors thank Christine Schmidt and Annika V\u00F6lkel for excellent technical assistance. The authors would like to thank the Flow Cytometry Core Facility of the Medical Faculty at the University of Bonn for providing support. The authors thank Jennifer Dietrich and Prof Daniela Wenzel for their excellent support in the establishment of ALI cultures. The authors acknowledge the HET and iFET facilities of the Medical Faculty, University of Bonn, as well as the Biological Research Facility, Bio21 Institute for Biotechnology and Molecular Science for their animal husbandry. The authors thank the Melbourne Cytometry Platform (Bio21 node) for provision of cytometry services. During the writing process of this work, the authors did not use generative AI or AI-assisted technologies.
Funding Information:
We thank Christine Schmidt and Annika V\u00F6lkel for excellent technical assistance. We would like to thank the Flow Cytometry Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeischaft (DFG, German Research Foundation) project-IDs: 387333827, 216372545, 216372401, 387335189, 471514137, 389568007. We thank Jennifer Dietrich and Prof. Daniela Wenzel for their excellent support in the establishment of ALI cultures. We acknowledge the HET and iFET facilities of the Medical Faculty, University of Bonn as well as the Biological Research Facility, Bio21 Institute for Biotechnology and Molecular Science for their animal husbandry. We thank the Melbourne Cytometry Platform (Bio21 node) for provision of cytometry services.
Publisher Copyright:
© 2024