Legionella pneumophila Exploits PI(4)P to Anchor Secreted Effector Proteins to the Replicative Vacuole
Open accessAbstract
The causative agent of Legionnaires' disease, Legionella pneumophila, employs the intracellular multiplication (Icm)/defective organelle trafficking (Dot) type IV secretion system (T4SS) to upregulate phagocytosis and to establish a replicative vacuole in amoebae and macrophages. Legionella-containing vacuoles (LCVs) do not fuse with endosomes but recruit early secretory vesicles. Here we analyze the role of host cell phosphoinositide (PI) metabolism during uptake and intracellular replication of L. pneumophila. Genetic and pharmacological evidence suggests that class I phosphatidylinositol(3) kinases (PI3Ks) are dispensable for phagocytosis of wild-type L. pneumophila but inhibit intracellular replication of the bacteria and participate in the modulation of the LCV. Uptake and degradation of an icmT mutant strain lacking a functional Icm/Dot transporter was promoted by PI3Ks. We identified Icm/Dot-secreted proteins which specifically bind to phosphatidylinositol(4) phosphate (PI(4)P) in vitro and preferentially localize to LCVs in the absence of functional PI3Ks. PI(4)P was found to be present on LCVs using as a probe either an antibody against PI(4)P or the PH domain of the PI(4)P-binding protein FAPP1 (phosphatidylinositol(4) phosphate adaptor protein-1). Moreover, the presence of PI(4)P on LCVs required a functional Icm/Dot T4SS. Our results indicate that L. pneumophila modulates host cell PI metabolism and exploits the Golgi lipid second messenger PI(4)P to anchor secreted effector proteins to the LCV.
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Several bacterial pathogens for humans, such as legionella, mycobacteria and salmonella, are pathogenic also for Dictyostelium.
“Several bacterial pathogens for humans, such as legionella, mycobacteria and salmonella, are pathogenic also for Dictyostelium, favouring the use of this model to study host-pathogen interactions [9-19].”
From Genome-wide transcriptional changes induced by phagocytosis or growth on bacteria in Dictyostelium (2008) · cites this paper as [17]
The Materials and Methods section (‘Intracellular growth of L. pneumophila within Dictyostelium’; page unavailable) describes infecting Dictyostelium with Legionella and measuring its intracellular replication, supporting that example and the model’s use in host–pathogen research. The passages from our copy do not establish that mycobacteria or salmonella are also pathogenic for Dictyostelium. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPI3K and PTEN, in contrast to PLC, are not essential for bacterial uptake, but pi3k1-2 null mutants are defective in phago-lysosomal maturation.
“PI3K and PTEN, in contrast to PLC, are not essential for bacterial uptake [5,73] [Balest, unpublished results], but pi3k1-2 null mutants are defective in phago-lysosomal maturation [17,74] [Balest, unpublished results].”
From Genome-wide transcriptional changes induced by phagocytosis or growth on bacteria in Dictyostelium (2008) · cites this paper as [17]
The citation to this paper is attached to the pi3k1-2 mutant maturation claim. Materials and Methods says the mutant is impaired in maturation of phagosomes into spacious phagosomes, and the Results report slower degradation of mutant L. pneumophila. Neither passage establishes a defect specifically in phago-lysosomal maturation. (LLM, conf=0.82)
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- Authors
- Weber, S. S., Ragaz, C., Reus, K., Nyfeler, Y., & Hilbi, H.
- Affiliations
- ETH Zurich (CH)
- Corresponding author
- Hilbi, Hubert
- ORCID
- Hilbi, Hubert
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-05-19
- Volume
- 2
- Issue
- 5
- Pages
- e46
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC1463015
- OpenAlex
- W1989102699
- Cited by
- 292
- References
- 58
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 16 · 2018: 11 · 2017: 20 · 2016: 14 · 2015: 19 · 2014: 24 · 2013: 26 · 2012: 22
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- National Science Foundation
- Velux Stiftung
- University of Dundee
- Oklahoma Medical Research Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (065952)
- Paul Scherrer Institut
- University of California, San Diego
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Microbiology › Microbial infections and disease research
- Keywords
- Legionella pneumophila, phosphatidylinositol 4-phosphate, type IV secretion system, effector proteins, Legionella-containing vacuole, phosphatidylinositol 3-kinase, phagocytosis, intracellular bacterial replication, Legionnaires' disease
- MeSH terms
- Animals, Bacterial Proteins, Cell Line, Dictyostelium, Humans, Molecular Sequence Data, Mutation, Phagocytosis, Tissue Distribution, Vacuoles, Organelles, Biomarkers, Legionella pneumophila, Phosphatidylinositol Phosphates, Phosphatidylinositol 3-Kinases, Protein Transport, Mice
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