Polyketide synthase (PKS) reduces fusion of Legionella pneumophila-containing vacuoles with lysosomes and contributes to bacterial competitiveness during infection

Shevchuk, Olga; Pägelow, Dennis; Rasch, Janine; Döhrmann, Simon; Günther, Gabriele; Hoppe, Julia; Ünal, Can; Bronietzki, Marc; Gutierrez, Maximiliano G.; Steinert, Michael

doi:10.1016/j.ijmm.2014.08.010

Cited by 12 publications

(19 citation statements)

References 89 publications

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“…1) while one other PKS derived compound has been implicated in lysosomal degradation (Shevchuk et al, 2014). Legioliulin is a trans -AT PKS derived fluorophore (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…From Legionella , only four BGCs have been explored in detail with three secondary metabolites structurally elucidated to date (Fig. 1) (Ahrendt et al, 2013; Shevchuk et al, 2014; Burnside et al, 2015; Johnston et al, 2016a). Legioliulin (1), a product of a trans -AT PKS cluster first identified in L. dumoffii, was reported originally in 2004 (Amemura-Maekawa et al, 2004) and biological activity assays failed to determine a role for the compound beyond fluorescence (Ahrendt et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…This study investigated the possibility that legioliulin is required for intracellular survival and ultimately failed to assign a biological function. On the other hand, a transposon mutagenesis library of L. pneumophila revealed a polyketide that interferes with lysosomal degradation during infection of both protozoa and macrophages (Shevchuk et al, 2014). Legiobactin (2) is a siderophore involved in iron sequestration (Cianciotto, 2007) and the unusual polyketide legionellol A (3) is involved in sliding motility and might additionally act as a surfactant (Johnston et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

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Legionellashows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase

Tobias

Ahrendt

Schell

et al. 2016

PeerJ

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Several members of the genus Legionella cause Legionnaires’ disease, a potentially debilitating form of pneumonia. Studies frequently focus on the abundant number of virulence factors present in this genus. However, what is often overlooked is the role of secondary metabolites from Legionella. Following whole genome sequencing, we assembled and annotated the Legionella parisiensis DSM 19216 genome. Together with 14 other members of the Legionella, we performed comparative genomics and analysed the secondary metabolite potential of each strain. We found that Legionella contains a huge variety of biosynthetic gene clusters (BGCs) that are potentially making a significant number of novel natural products with undefined function. Surprisingly, only a single Sfp-like phosphopantetheinyl transferase is found in all Legionella strains analyzed that might be responsible for the activation of all carrier proteins in primary (fatty acid biosynthesis) and secondary metabolism (polyketide and non-ribosomal peptide synthesis). Using conserved active site motifs, we predict some novel compounds that are probably involved in cell-cell communication, differing to known communication systems. We identify several gene clusters, which may represent novel signaling mechanisms and demonstrate the natural product potential of Legionella.

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“…1) while one other PKS derived compound has been implicated in lysosomal degradation (Shevchuk et al, 2014). Legioliulin is a trans -AT PKS derived fluorophore (Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Legionellashows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase

Tobias

Ahrendt

Schell

et al. 2016

PeerJ

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“…The major outer membrane protein (MOMP) of L. pneumophila binds complement component C3 and C3i and mediates the uptake of the bacteria via the complement receptors CR1 and CR3 of macrophages. Phagocytosed L. pneumophila recruit compartments from the endoplasmatic reticulum (ER), modulate the host phosphoinositide metabolism, modify the host endocytic pathway, intercept vesicle trafficking and avoid fusion with lysosomes (Shevchuk et al, 2014). The development of the Legionella -containing vacuole (LCV) is pre-dominantly orchestrated by the Dot/Icm type IV secretion system, which is known to export numerous bacterial effector proteins into the host cell cytoplasm (Horwitz, 1983; Kagan and Roy, 2002; Isberg et al, 2009; Hubber and Roy, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study, we screened a L. pneumophila mini-Tn10 transposon library for mutants that fail to avoid fusion of their respective LCV with lysosomes (Shevchuk et al, 2014). The range of the identified mutants indicated that interference with lysosomal degradation is multifactorial.…”

Section: Introductionmentioning

confidence: 99%

PilY1 Promotes Legionella pneumophila Infection of Human Lung Tissue Explants and Contributes to Bacterial Adhesion, Host Cell Invasion, and Twitching Motility

Hoppe

Ünal

Thiem

et al. 2017

Front. Cell. Infect. Microbiol.

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Legionnaires' disease is an acute fibrinopurulent pneumonia. During infection Legionella pneumophila adheres to the alveolar lining and replicates intracellularly within recruited macrophages. Here we provide a sequence and domain composition analysis of the L. pneumophila PilY1 protein, which has a high homology to PilY1 of Pseudomonas aeruginosa. PilY1 proteins of both pathogens contain a von Willebrand factor A (vWFa) and a C-terminal PilY domain. Using cellular fractionation, we assigned the L. pneumophila PilY1 as an outer membrane protein that is only expressed during the transmissive stationary growth phase. PilY1 contributes to infection of human lung tissue explants (HLTEs). A detailed analysis using THP-1 macrophages and A549 lung epithelial cells revealed that this contribution is due to multiple effects depending on host cell type. Deletion of PilY1 resulted in a lower replication rate in THP-1 macrophages but not in A549 cells. Further on, adhesion to THP-1 macrophages and A549 epithelial cells was decreased. Additionally, the invasion into non-phagocytic A549 epithelial cells was drastically reduced when PilY1 was absent. Complementation variants of a PilY1-negative mutant revealed that the C-terminal PilY domain is essential for restoring the wild type phenotype in adhesion, while the putatively mechanosensitive vWFa domain facilitates invasion into non-phagocytic cells. Since PilY1 also promotes twitching motility of L. pneumophila, we discuss the putative contribution of this newly described virulence factor for bacterial dissemination within infected lung tissue.

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Acyl Histidines: New N‐Acyl Amides from Legionella pneumophila

Tørring¹,

Shames

Cho

et al. 2017

ChemBioChem

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Legionella pneumophila, the causative agent of Legionnaires’ disease, is a Gram-negative Gammaproteobacterial pathogen that infects and intracellularly replicates in human macrophages and a variety of protozoa. L. pneumophila encodes an orphan biosynthetic gene cluster (BGC) that contains isocyanide-associated biosynthetic genes and is upregulated during infection. Because isocyanide-functionalized metabolites are known to harbor invertebrate innate immunosuppressive activities in bacterial pathogen-insect interactions, we used pathway-targeted molecular networking and tetrazine-based chemoseletive ligation chemistry to characterize the metabolites from the orphan pathway in L. pneumophila. We also assessed their intracellular growth contributions in an amoeba and in murine bone marrow derived macrophages. Unexpectedly, two distinct groups of aromatic amino acid-derived metabolites were identified from the pathway, including a known tyrosine-derived isocyanide and a family of new N-acyl-L-histidine metabolites.

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Polyketide synthase (PKS) reduces fusion of Legionella pneumophila-containing vacuoles with lysosomes and contributes to bacterial competitiveness during infection

Abstract: CitationPolyketide synthase (PKS) reduces fusion of Legionella pneumophila-containing vacuoles with lysosomes and contributes to bacterial competitiveness during infection.

Cited by 12 publications

References 89 publications

Legionellashows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase

Legionellashows a diverse secondary metabolism dependent on a broad spectrum Sfp-type phosphopantetheinyl transferase

PilY1 Promotes Legionella pneumophila Infection of Human Lung Tissue Explants and Contributes to Bacterial Adhesion, Host Cell Invasion, and Twitching Motility

Acyl Histidines: New N‐Acyl Amides from Legionella pneumophila

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