The presence of professional phagocytes dictates the number of host cells targeted for Yop translocation during infection

Durand, Enrique; Maldonado-Arocho, Francisco J.; Castillo, Cynthia; Walsh, Rebecca L.; Mecsas, Joan

doi:10.1111/j.1462-5822.2010.01451.x

Cited by 72 publications

(122 citation statements)

References 43 publications

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“…In a mouse model, Y. pseudotuberculosis yadA mutants can still cause a systemic infection but with significantly lower numbers of bacteria in systemic organs (36). A role for YadA in persistence and systemic dissemination has been shown to occur in cooperation with the Ail adhesion (37) and involves an interaction with neutrophils (38). Based on this finding, we speculate that a downregulation of YadA expression could constitute an impediment during the initial in vivo colonization by the ⌬tatC mutant.…”

Section: Figmentioning

confidence: 76%

Transcriptomic and Phenotypic Analysis Reveals New Functions for the Tat Pathway in Yersinia pseudotuberculosis

et al. 2016

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The twin-arginine translocation (Tat) system mediates the secretion of folded proteins that are identified via an N-terminal signal peptide in bacteria, plants, and archaea. Tat systems are associated with virulence in many bacterial pathogens, and our previous studies revealed that Tat-deficient Yersinia pseudotuberculosis was severely attenuated for virulence. Aiming to identify Tat-dependent pathways and phenotypes of relevance for in vivo infection, we analyzed the global transcriptome of parental and ⌬tatC mutant strains of Y. pseudotuberculosis during exponential and stationary growth at 26°C and 37°C. The most significant changes in the transcriptome of the ⌬tatC mutant were seen at 26°C during stationary-phase growth, and these included the altered expression of genes related to virulence, stress responses, and metabolism. Subsequent phenotypic analysis based on these transcriptome changes revealed several novel Tat-dependent phenotypes, including decreased YadA expression, impaired growth under iron-limited and high-copper conditions, as well as acidic pH and SDS. Several functionally related Tat substrates were also verified to contribute to these phenotypes. Interestingly, the phenotypic defects observed in the Tat-deficient strain were generally more pronounced than those in mutants lacking the Tat substrate predicted to contribute to that specific function. Altogether, this provides new insight into the impact of Tat deficiency on in vivo fitness and survival/replication of Y. pseudotuberculosis during infection. IMPORTANCEIn addition to its established role in mediating the secretion of housekeeping enzymes, the Tat system has been recognized as being involved in infection. In some clinically relevant bacteria, such as Pseudomonas spp., several key virulence determinants can readily be identified among the Tat substrates. In enteropathogens, such as Yersinia spp., there are no obvious virulence determinants among the Tat substrates. Tat mutants show no growth defect in vitro but are highly attenuated in in vivo. This makes Tat an attractive target for the development of novel antimicrobials. Therefore, it is important to establish the causes of the attenuation. Here, we show that the attenuation is likely due to synergistic effects of different Tat-dependent phenotypes that each contributes to lowered in vivo fitness. Bacteria have evolved several specialized secretion systems for protein export as part of their successful strategies to colonize niches where they encounter various environmental conditions. Gram-negative bacteria possess different mechanisms to transport/export proteins, including virulence-related factors from the cytoplasm across the inner membrane and/or the outer membrane, either in a single step or acting together with other secretion systems (1). Two pathways, the secretory (Sec) and the twin-arginine translocation (Tat) pathways, are involved in the translocation of proteins from the cytoplasm to the periplasm. In Gramnegative bacteria, they can cooperate with other s...

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Section: Figmentioning

confidence: 76%

Transcriptomic and Phenotypic Analysis Reveals New Functions for the Tat Pathway in Yersinia pseudotuberculosis

et al. 2016

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“…The main target cells for Y. pseudotuberculosis T3SS-mediated Yop translocation during infection are polymorphonuclear cells or neutrophils (PMNs) (8), suggesting that these innate immune cells play a key role in combating the infection. PMNs are rapidly recruited to infection sites in response to host-and pathogenderived chemotactic factors (9).…”

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confidence: 99%

Role of YopK in Yersinia pseudotuberculosis Resistance against Polymorphonuclear Leukocyte Defense

et al. 2013

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The enteropathogen Yersinia pseudotuberculosis can survive in the harsh environment of lymphoid compartments that abounds in immune cells. This capacity is dependent on the plasmid-encoded Yersinia outer proteins (Yops) that are delivered into the host cell via a mechanism involving the Yersinia type III secretion system. We show that the virulence protein YopK has a role in the mechanism by which Y. pseudotuberculosis avoids the polymorphonuclear leukocyte or neutrophil (PMN) defense. A yopK mutant, which is attenuated in the mouse infection model, where it fails to cause systemic infection, was found to colonize Peyer's patches and mesenteric lymph nodes more rapidly than the wild-type strain. Further, in mice lacking PMNs, the yopK mutant caused full disease with systemic spread and typical symptoms. Analyses of effects on PMNs revealed that both the wild-type strain and the yopK mutant inhibited internalization and reactive oxygen species production, as well as neutrophil extracellular trap formation by PMNs. However, the wild-type strain effectively avoided induction of PMN death, whereas the mutant caused a necrosis-like PMN death. Taken together, our results indicate that YopK is required for the ability of Yersinia to resist the PMN defense, which is critical for the virulence of the pathogen. We suggest a mechanism whereby YopK functions to prevent unintended Yop delivery and thereby PMN disruption, resulting in necrosis-like cell death, which would enhance the inflammatory response favoring the host.

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“…Previous studies on translocation of effector proteins have shown that the FRET-based β-lactamase reporter assay is compatible with analysis by flow cytometry. [10][11][12] In the present report we show that our vacuolar rupture assay can also be analyzed by flow cytometry, which constitutes an important alternative and complementary read-out to microscopy-based data acquisition. Figure 1.…”

Section: Experimental Approachmentioning

confidence: 70%

“…7 Recently, this assay has been adapted to measure effector translocation or internalization of invasive bacteria in vitro and in vivo by creating β-lactamase fusion proteins with bacterial effectors. [8][9][10][11][12][13] Using Shigella invasion of host cells as a model system, we have extended these approaches by establishing a novel fluorescence microscopy assay that allows the study of vacuole rupture with high spatiotemporal precision (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

MonitoringShigella flexnerivacuolar escape by flow cytometry

Nothelfer¹,

Rodrigues²,

Bobard³

et al. 2011

Virulence

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The presence of professional phagocytes dictates the number of host cells targeted for Yop translocation during infection

Cited by 72 publications

References 43 publications

Transcriptomic and Phenotypic Analysis Reveals New Functions for the Tat Pathway in Yersinia pseudotuberculosis

Transcriptomic and Phenotypic Analysis Reveals New Functions for the Tat Pathway in Yersinia pseudotuberculosis

Role of YopK in Yersinia pseudotuberculosis Resistance against Polymorphonuclear Leukocyte Defense

MonitoringShigella flexnerivacuolar escape by flow cytometry

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