Sel1 Repeat Protein LpnE Is a
            <i>Legionella pneumophila</i>
            Virulence Determinant That Influences Vacuolar Trafficking

Newton, Hayley J; Sansom, Fiona M.; Dao, Jenny; McAlister, Adrian Dale; Sloan, Joan; Cianciotto, Nicholas P.; Hartland, Elizabeth L.

doi:10.1128/iai.00443-07

Cited by 89 publications

(111 citation statements)

References 56 publications

(60 reference statements)

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“…Several "Ca. Amoebophilus asiaticus" SEL1 repeat proteins show high similarity (up to 52% amino acid identity) to L. pneumophila LidL, which has been shown to be important in early signaling events regulating intracellular trafficking of L. pneumophila in macrophages (21,22,84). The "Ca.…”

Section: Resultsmentioning

confidence: 99%

“…Amoebophilus asiaticus" encodes 129 proteins (8% of all CDSs) with domains predominantly found in eukaryotic proteins, including ankyrin repeats, TPR/SEL1 repeats, leucinerich repeats, or F-and U-box domains (see Tables S2 to S6 in the supplemental material). These domains can mediate protein-protein interactions and are particularly important for the interaction of various intracellular bacterial pathogens with their eukaryotic host cells (3,17,18,40,65,84,91,120). Compared to all other bacteria for which genome sequences are available, the number and percentage of proteins with eukaryotic domains in the "Ca.…”

Section: Resultsmentioning

confidence: 99%

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The Genome of the Amoeba Symbiont “CandidatusAmoebophilus asiaticus” Reveals Common Mechanisms for Host Cell Interaction among Amoeba-Associated Bacteria

et al. 2010

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Protozoa play host for many intracellular bacteria and are important for the adaptation of pathogenic bacteria to eukaryotic cells. We analyzed the genome sequence of "Candidatus Amoebophilus asiaticus," an obligate intracellular amoeba symbiont belonging to the Bacteroidetes. The genome has a size of 1.89 Mbp, encodes 1,557 proteins, and shows massive proliferation of IS elements (24% of all genes), although the genome seems to be evolutionarily relatively stable. The genome does not encode pathways for de novo biosynthesis of cofactors, nucleotides, and almost all amino acids. "Ca. Amoebophilus asiaticus" encodes a variety of proteins with predicted importance for host cell interaction; in particular, an arsenal of proteins with eukaryotic domains, including ankyrin-, TPR/SEL1-, and leucine-rich repeats, which is hitherto unmatched among prokaryotes, is remarkable. Unexpectedly, 26 proteins that can interfere with the host ubiquitin system were identified in the genome. These proteins include F-and U-box domain proteins and two ubiquitin-specific proteases of the CA clan C19 family, representing the first prokaryotic members of this protein family. Consequently, interference with the host ubiquitin system is an important host cell interaction mechanism of "Ca. Amoebophilus asiaticus". More generally, we show that the eukaryotic domains identified in "Ca. Amoebophilus asiaticus" are also significantly enriched in the genomes of other amoeba-associated bacteria (including chlamydiae, Legionella pneumophila, Rickettsia bellii, Francisella tularensis, and Mycobacterium avium). This indicates that phylogenetically and ecologically diverse bacteria which thrive inside amoebae exploit common mechanisms for interaction with their hosts, and it provides further evidence for the role of amoebae as training grounds for bacterial pathogens of humans.Free-living amoebae, such as Acanthamoeba spp., are ubiquitous protozoa which can be found in such diverse habitats as soil, marine water, and freshwater and in many engineered environments (62, 100). They are important predators of prokaryotic and eukaryotic microorganisms, thereby having great influence on microbial community composition, soil mineralization, plant growth, and nutrient cycles (14, 100). Interestingly, many well-known pathogens of humans are able to infect, survive, and multiply within amoebae (39, 51). These protozoa can thus serve as reservoirs and vectors for the transmission of pathogenic bacteria to humans, as demonstrated for L. pneumophila and Mycobacterium avium (2, 115). It is also increasingly being recognized that protozoa are important for the adaptation of (pathogenic) bacteria to higher eukaryotic cells as a niche for growth (2,24,42,78,89).In addition to the many recognized transient associations between amoeba and pathogens, stable and obligate relationships between bacteria and amoebae also were described for members of the Alphaproteobacteria (11, 34, 48), the Betaproteobacteria (49), the Bacteroidetes (50), and the Chlamydiae (4, 12, 35, 52...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Genome of the Amoeba Symbiont “CandidatusAmoebophilus asiaticus” Reveals Common Mechanisms for Host Cell Interaction among Amoeba-Associated Bacteria

et al. 2010

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“…After 72 h, bacteria are gradually cleared from the lungs of A/J mice without overt signs of illness (59). This model has been used previously to test isogenic mutants of L. pneumophila for a role in virulence (40,60). Here 6 -8-week-old A/J mice were infected with a 1:1 ratio of wild type L. pneumophila FIGURE 5.…”

Section: Mutation Of Conserved Residues Present In the Acrs Affects Tmentioning

confidence: 99%

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

Sansom

Riedmaier

Newton

et al. 2008

Journal of Biological Chemistry

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Legionella pneumophila is the predominant cause of Legionnaires disease, a severe and potentially fatal form of pneumonia. Recently, we identified an ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila, termed Lpg1905, which enhances intracellular replication of L. pneumophila in eukaryotic cells. Lpg1905 is the first prokaryotic member of the CD39/NTPDase1 family of enzymes, which are characterized by the presence of five apyrase conserved regions and the ability to hydrolyze nucleoside tri-and diphosphates. Here we examined the substrate specificity of Lpg1905 and showed that apart from ATP and ADP, the enzyme catalyzed the hydrolysis of GTP and GDP but had limited activity against CTP, CDP, UTP, and UDP. Based on amino acid residues conserved in the apyrase conserved regions of eukaryotic NTPDases, we generated five site-directed mutants, Lpg1905E159A, R122A, N168A, Q193A, and W384A. Although the mutations E159A, R122A, Q193A, and W384A abrogated activity completely, N168A resulted in decreased activity caused by reduced affinity for nucleotides. When introduced into the lpg1905 mutant strain of L. pneumophila, only N168A partially restored the ability of L. pneumophila to replicate in THP-1 macrophages. Following intratracheal inoculation of A/J mice, none of the Lpg1905 mutants was able to restore virulence to an lpg1905 mutant during lung infection, thereby demonstrating the importance of NTPDase activity to L. pneumophila infection. Overall, the kinetic studies undertaken here demonstrated important differences to mammalian NTPDases and different sensitivities to NTPDase inhibitors that may reflect underlying structural variations.Legionella pneumophilia is the major causative agent of Legionnaires disease, a severe systemic disease characterized by acute pneumonia. During infection of the human lung, L. pneumophila is internalized by alveolar macrophages where the bacteria replicate within an intracellular vacuole that evades fusion with the endocytic pathway. Instead the L. pneumophila containing vacuole intercepts early secretory vesicles and following maturation exhibits properties of the endoplasmic reticulum (1-3). Establishment of the unique Legionella vacuole and the ability to replicate within eukaryotic cells requires the Dot/Icm type IV secretion system, which translocates bacterial effector proteins into the cytoplasm of the host cell (4 -7).The ability of L. pneumophila to replicate within mammalian cells appears to be a consequence of its association in the natural environment with free living protozoa. The three sequenced L. pneumophila genomes encode an unusually high number of proteins with similarity to eukaryotic proteins (8 -10), which may interfere with host cell processes by functional mimicry (11). We recently showed that Lpg1905 from L. pneumophila is a secreted member of the CD39/ NTPDase1 family of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases; gene family ENTPD).5 NTPDases are extremely rare in bacteria, and Lpg1905 is the first prokaryotic...

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“…3D), a SEL1 repeatcontaining protein that interacts with eukaryotic Nek9, Hsp90, and Hsc71 (37). L. pneumophila produces two SEL1-containing proteins, L. pneumophila Entry (LpnE) and Enhanced Entry protein C (EnhC), involved in bacterial uptake by susceptible host cells (38,39). EnhC is also required for proper intracellular growth under stress conditions, including tumor necrosis factor alpha (TNF-␣) treatment, and dampens Nod1-dependent activation of the host transcription factor NF-B, effectively downregulating a detrimental immune response (40).…”

Section: Resultsmentioning

confidence: 99%

Refining the Plasmid-Encoded Type IV Secretion System Substrate Repertoire of Coxiella burnetii

Maturana¹,

Graham²,

Sharma³

et al. 2013

Journal of Bacteriology

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The intracellular bacterial agent of Q fever, Coxiella burnetii, translocates effector proteins into its host cell cytosol via a Dot/ Icm type IV secretion system (T4SS). The T4SS is essential for parasitophorous vacuole formation, intracellular replication, and inhibition of host cell death, but the effectors mediating these events remain largely undefined. Six Dot/Icm substrate-encoding genes were recently discovered on the C. burnetii cryptic QpH1 plasmid, three of which are conserved among all C. burnetii isolates, suggesting that they are critical for conserved pathogen functions. However, the remaining hypothetical proteins encoded by plasmid genes have not been assessed for their potential as T4SS substrates. In the current study, we further defined the T4SS effector repertoire encoded by the C. burnetii QpH1, QpRS, and QpDG plasmids that were originally isolated from acute-disease, chronic-disease, and severely attenuated isolates, respectively. Hypothetical proteins, including those specific to QpRS or QpDG, were screened for translocation using the well-established Legionella pneumophila T4SS secretion model. In total, six novel plasmid-encoded proteins were translocated into macrophage-like cells by the Dot/Icm T4SS. Four newly identified effectors are encoded by genes present only on the QpDG plasmid from severely attenuated Dugway isolates, suggesting that the presence of specific effectors correlates with decreased virulence. These results further support the idea of a critical role for extrachromosomal elements in C. burnetii pathogenesis.

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Sel1 Repeat Protein LpnE Is a Legionella pneumophila Virulence Determinant That Influences Vacuolar Trafficking

Cited by 89 publications

References 56 publications

The Genome of the Amoeba Symbiont “CandidatusAmoebophilus asiaticus” Reveals Common Mechanisms for Host Cell Interaction among Amoeba-Associated Bacteria

The Genome of the Amoeba Symbiont “CandidatusAmoebophilus asiaticus” Reveals Common Mechanisms for Host Cell Interaction among Amoeba-Associated Bacteria

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

Refining the Plasmid-Encoded Type IV Secretion System Substrate Repertoire of Coxiella burnetii

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