Molecular mimicry and original biochemical strategies for the biogenesis of a Legionella pneumophila replicative niche in phagocytic cells

Allombert, Julie; Fuche, Fabien J.; Michard, Céline; Doublet, Patricia

doi:10.1016/j.micinf.2013.09.007

Cited by 16 publications

(11 citation statements)

References 76 publications

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“…Most of this work has relied on the construction of deletion mutants for the corresponding T4SS substrates. However, because of functional redundancy between effectors, single gene deletions very rarely result in a virulence defect; consequently, to date, only a few T4SS effectors have been functionally characterized (for reviews, see references 5 to 9 ). Among these are proteins that interfere with small GTPases of the early secretory cellular pathway ( 10 – 17 ), the endocytic pathway ( 18 ), or the retrograde vesicle trafficking ( 19 ) or target the innate immune response and host cell apoptosis pathways ( 7 , 20,21 ).…”

Section: Introductionmentioning

confidence: 99%

The Legionella Kinase LegK2 Targets the ARP2/3 Complex To Inhibit Actin Nucleation on Phagosomes and Allow Bacterial Evasion of the Late Endocytic Pathway

Michard

Spérandio

Baïlo

et al. 2015

mBio

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Legionella pneumophila, the etiological agent of legionellosis, replicates within phagocytic cells. Crucial to biogenesis of the replicative vacuole is the Dot/Icm type 4 secretion system, which translocates a large number of effectors into the host cell cytosol. Among them is LegK2, a protein kinase that plays a key role in Legionella infection. Here, we identified the actin nucleator ARP2/3 complex as a target of LegK2. LegK2 phosphorylates the ARPC1B and ARP3 subunits of the ARP2/3 complex. LegK2-dependent ARP2/3 phosphorylation triggers global actin cytoskeleton remodeling in cells, and it impairs actin tail formation by Listeria monocytogenes, a well-known ARP2/3-dependent process. During infection, LegK2 is addressed to the Legionella-containing vacuole surface and inhibits actin polymerization on the phagosome, as revealed by legK2 gene inactivation. Consequently, LegK2 prevents late endosome/lysosome association with the phagosome and finally contributes to remodeling of the bacterium-containing phagosome into a replicative niche. The inhibition of actin polymerization by LegK2 and its effect on endosome trafficking are ARP2/3 dependent since it can be phenocopied by a specific chemical inhibitor of the ARP2/3 complex. Thus, LegK2-ARP2/3 interplay highlights an original mechanism of bacterial virulence with an unexpected role in local actin remodeling that allows bacteria to control vesicle trafficking in order to escape host defenses.

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Section: Introductionmentioning

confidence: 99%

The Legionella Kinase LegK2 Targets the ARP2/3 Complex To Inhibit Actin Nucleation on Phagosomes and Allow Bacterial Evasion of the Late Endocytic Pathway

Michard

Spérandio

Baïlo

et al. 2015

mBio

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“…L. pneumophila are subject to predation by eukaryotic phagocytes, such as amoeba and ciliates, so the bacterium's survival and spread depends on the ability to hijack the phagocytic vacuole, to create a replicative niche, to prevent phagosome-lysosome fusion and evade host immune system. In humans, L. pneumophila reaches the lungs after inhalation of contaminated aerosol droplets where the similar mechanisms allow L. pneumophila to hijack another phagocyte, lung-based macrophages, leading to infection [2] – [10] . Since human-to-human transmission of L. pneumophila has not been observed the human infection is an evolutive dead end for Legionella .…”

Section: Introductionmentioning

confidence: 99%

Intragenic Recombination Has a Critical Role on the Evolution of Legionella pneumophila Virulence-Related Effector sidJ

et al. 2014

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SidJ is a Dot/Icm effector involved in the trafficking or retention of ER-derived vesicles to Legionella pneumophila vacuoles whose mutation causes an observable growth defect, both in macrophage and amoeba hosts. Given the crucial role of this effector in L. pneumophila virulence we investigated the mechanisms shaping its molecular evolution. The alignment of SidJ sequences revealed several alleles with amino acid variations that may influence the protein properties. The identification of HGT events and the detection of balancing selection operating on sidJ evolution emerge as a clear result. Evidence suggests that intragenic recombination is an important strategy in the evolutionary adaptive process playing an active role on sidJ genetic plasticity. This pattern of evolution is in accordance with the life style of L. pneumophila as a broad host-range pathogen by preventing host-specialization and contributing to the resilience of the species.

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“…In L. pneumophila, a T2SS and a T4SS were identified several years ago (7)(8)(9) and their implication in the virulence of this bacterium has been extensively studied (10,11). T4SS Dot/Icm has been particularly well investigated, as it is responsible for the translocation of more than 275 effector proteins into the cytoplasm of infected cells (12,13). Those effectors are required for the entire intracellular cycle of L. pneumophila, as they are involved in the creation of a replicative niche inside the host cell, called a Legionella-containing vacuole (LCV), that is suitable for bacterial replication.…”

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confidence: 99%

Functional Type 1 Secretion System Involved in Legionella pneumophila Virulence

et al. 2014

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e Legionella pneumophila is a Gram-negative pathogen found mainly in water, either in a free-living form or within infected protozoans, where it replicates. This bacterium can also infect humans by inhalation of contaminated aerosols, causing a severe form of pneumonia called legionellosis or Legionnaires' disease. The involvement of type II and IV secretion systems in the virulence of L. pneumophila is now well documented. Despite bioinformatic studies showing that a type I secretion system (T1SS) could be present in this pathogen, the functionality of this system based on the LssB, LssD, and TolC proteins has never been established. Here, we report the demonstration of the functionality of the T1SS, as well as its role in the infectious cycle of L. pneumophila. Using deletion mutants and fusion proteins, we demonstrated that the repeats-in-toxin protein RtxA is secreted through an LssB-LssD-TolC-dependent mechanism. Moreover, fluorescence monitoring and confocal microscopy showed that this T1SS is required for entry into the host cell, although it seems dispensable to the intracellular cycle. Together, these results underline the active participation of L. pneumophila, via its T1SS, in its internalization into host cells.

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Molecular mimicry and original biochemical strategies for the biogenesis of a Legionella pneumophila replicative niche in phagocytic cells

Cited by 16 publications

References 76 publications

The Legionella Kinase LegK2 Targets the ARP2/3 Complex To Inhibit Actin Nucleation on Phagosomes and Allow Bacterial Evasion of the Late Endocytic Pathway

The Legionella Kinase LegK2 Targets the ARP2/3 Complex To Inhibit Actin Nucleation on Phagosomes and Allow Bacterial Evasion of the Late Endocytic Pathway

Intragenic Recombination Has a Critical Role on the Evolution of Legionella pneumophila Virulence-Related Effector sidJ

Functional Type 1 Secretion System Involved in Legionella pneumophila Virulence

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