Regulation of Legionella Phagosome Maturation and Infection through Flagellin and Host Ipaf
Open accessAbstract
Legionella pneumophila is an intracellular bacterium that causes an acute form of pneumonia called Legionnaires' disease. After infection of human macrophages, the Legionella-containing phagosome (LCP) avoids fusion with the lysosome allowing intracellular replication of the bacterium. In macrophages derived from most mouse strains, the LCP is delivered to the lysosome resulting in Legionella degradation and restricted bacterial growth. Mouse macrophages lacking the NLR protein Ipaf or its downstream effector caspase-1 are permissive to intracellular Legionella replication. However, the mechanism by which Ipaf restricts Legionella replication is not well understood. Here we demonstrate that the presence of flagellin and a competent type IV secretion system are critical for Legionella to activate caspase-1 in macrophages. Activation of caspase-1 in response to Legionella infection also required host Ipaf, but not TLR5. In the absence of Ipaf or caspase-1 activation, the LCP acquired endoplasmic reticulum-derived vesicles, avoided fusion with the lysosome, and allowed Legionella replication. Accordingly a Legionella mutant lacking flagellin did not activate caspase-1, avoided degradation, and replicated in wild-type macrophages. The regulation of phagosome maturation by Ipaf occurred within 2 h after infection and was independent of macrophage cell death. In vivo studies confirmed that flagellin and Ipaf play an important role in the control of Legionella clearance. These results reveal that Ipaf restricts Legionella replication through the regulation of phagosome maturation, providing a novel function for NLR proteins in host defense against an intracellular bacterium.
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IL-1β production was independent of the Ipaf inflammasome.
“By contrast, IL-1β production was independent of the Ipaf inflammasome, which has been shown to activate caspase-1 and produce IL-1β in response to flagellin from Salmonella typhimurium and Legionella pneumophila (fig.S4) (11,12).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [12]
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- Authors
- Amer, A., Franchi, L., Kanneganti, T.-D., Body-Malapel, M., Özören, N., Brady, G., Meshinchi, S., Jagirdar, R., Gewirtz, A., Akira, S., & Núñez, G.
- Affiliations
- University of Michigan (US)
- Emory University (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Núñez, Gabriel
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 281
- Issue
- 46
- Pages
- 35217-35223
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2157783137
- Cited by
- 453
- References
- 37
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 16 · 2022: 13 · 2021: 19 · 2020: 15 · 2019: 13 · 2018: 18 · 2017: 21 · 2016: 23 · 2015: 16 · 2014: 25 · 2013: 36 · 2012: 33
- FWCI
- 19.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007517)
- National Institute of Allergy and Infectious Diseases (AI 064748, AI063331, R01AI064748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Legionella pneumophila, phagosome maturation, flagellin, interstitial pneumonia with autoimmune features, caspase-1, type IV secretion system, macrophages, Legionnaires' disease, NLR proteins, intracellular bacterial replication
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Bone Marrow Cells, Calcium-Binding Proteins, Carrier Proteins, Endoplasmic Reticulum, Enzyme Activation, Flagellin, Gene Expression Regulation, Macrophages, Phagosomes, Legionella pneumophila, Mice, Knockout, Caspase 1, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Mice, Nod1 Signaling Adaptor Protein
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