<i>Y</i><i>ersinia pseudotuberculosis</i>uses Ail and YadA to circumvent neutrophils by directing Yop translocation during lung infection

Paczosa, Michelle K.; Fisher, Michael L.; Maldonado-Arocho, Francisco J.; Mecsas, Joan

doi:10.1111/cmi.12219

Cited by 29 publications

(38 citation statements)

References 88 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: 75%

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: 75%

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

et al. 2016

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“…The cytotoxic necrotizing factor CNFγ acts as toxin and is an essential virulence determinant, as it modulates inflammatory responses and counteracts attack by innate immune effectors (36,37). Similar to YadA, the adhesin AilA promotes binding to and subsequent killing of neutrophils via type III secretion-mediated translocation of effector proteins into the target host cell and promotes resistance against complement-mediated killing (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

Righetti

Nuss

Twittenhoff

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

136

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RNA structures are fundamentally important for RNA function. Dynamic, condition-dependent structural changes are able to modulate gene expression as shown for riboswitches and RNA thermometers. By parallel analysis of RNA structures, we mapped the RNA structurome of Yersinia pseudotuberculosis at three different temperatures. This human pathogen is exquisitely responsive to host body temperature (37°C), which induces a major metabolic transition. Our analysis profiles the structure of more than 1,750 RNAs at 25°C, 37°C, and 42°C. Average mRNAs tend to be unstructured around the ribosome binding site. We searched for 5′-UTRs that are folded at low temperature and identified novel thermoresponsive RNA structures from diverse gene categories. The regulatory potential of 16 candidates was validated. In summary, we present a dynamic bacterial RNA structurome and find that the expression of virulence-relevant functions in Y. pseudotuberculosis and reprogramming of its metabolism in response to temperature is associated with a restructuring of numerous mRNAs.RNA structure | RNA thermometer | temperature | virulence | translational control R NA structures play a pivotal role in the function of noncoding RNAs (ncRNAs) comprised of rRNAs, tRNAs, and small regulatory RNAs (sRNAs) and in the expression of proteincoding mRNAs. Structured segments affect the entire RNA life cycle from transcription, maturation, and translation to degradation and determine the specificity of interactions with other RNAs, proteins, or ligands. Although some RNAs, such as ribozymes and rRNAs, adopt rather stable secondary and tertiary structures, many regulatory RNA elements are dynamic and undergo structural rearrangements in the physiological temperature range. Well-known examples are metabolite-sensing riboswitches (1) and temperaturesensing RNA thermometers (RNATs) (2). Bacterial RNATs are usually located in the 5′-UTR or the intercistronic region (ICR) of an mRNA and differentially control translation of the downstream ORF in response to temperature (3). Typically, an RNAT folds into a structure that occludes the ribosome binding site (RBS). A temperature upshift liberates the RBS and allows the ribosome to bind and initiate translation. Structurally diverse RNATs are located upstream of many bacterial heat shock and virulence genes. Thermosensitive RNA structures playing a role in infection and host adaptation processes have been documented in Listeria monocytogenes (4), Yersinia pestis (5), Yersinia pseudotuberculosis (6), Leptospira interrogans (7), Shigella dysenteriae (8), Neisseria meningitidis (9), Pseudomonas aeruginosa (10), and Vibrio cholerae (11).In contrast to ligand-binding riboswitches, RNATs show poor, if any, conservation in sequence and structure. This diversity has hampered the in silico identification of novel RNATs, but recently developed genome-wide RNA structure-probing approaches offer new opportunities (12). Global structure probing maps the structures of the entire pool of expressed RNA molecules and provides a sna...

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“…In addition, Ail seemed necessary for specifically targeting neutrophils for T3SS translocation of effectors in the lungs when animals were infected intranasally with either the WT strain or the ⌬ail mutant of Y. pseudotuberculosis (71). In our study, the lungs of the triple mutant-infected animals had minimal to mild neutrophilic inflammation on day 2 p.i.…”

Section: Discussionmentioning

confidence: 49%

Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague

et al. 2015

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f Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated Yersinia pestis CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the ail gene (encoding the attachment-invasion locus) from wild-type (WT) strain CO92 or its lpp single and ⌬lpp ⌬msbB double mutants. While the ⌬ail single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the ⌬lpp ⌬ail double mutant and the ⌬lpp ⌬msbB ⌬ail triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD 50 ) equivalent to 6,800 LD 50 s of WT CO92. The mutant-infected animals developed balanced T H 1-and T H 2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD 50 s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by in vivo imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the ail gene from the ⌬lpp ⌬msbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection. P athogenic yersiniae lead to two types of diseases: yersiniosis (typified by gastroenteritis caused by Yersinia enterocolitica and Y. pseudotuberculosis) (1) and plague (evoked by Y. pestis) (2, 3). Y. pestis has evolved from Y. pseudotuberculosis within the last 20,000 years by acquiring additional plasmids and pathogenicity islands as well as by deactivating some genes (4-6). This evolutionary adaptation allowed the plague bacterium to maintain a dual life-style in fleas and rodents/mammals and conferred the ability to survive in the blood instead of the intestine (3). Plague manifests itself in three forms: bubonic (acquired from an infected rodent through a flea bite), pneumonic (acquired either directly by aerosol transmission from an infected host's lungs through respiratory droplets or secondarily from bubonic plague), and septicemic (severe bacteremia either directly due to a flea bite or subsequent to bubonic or pneumonic plague) (2). T...

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Yersinia pseudotuberculosisuses Ail and YadA to circumvent neutrophils by directing Yop translocation during lung infection

Cited by 29 publications

References 88 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

Temperature-responsive in vitro RNA structurome of Yersinia pseudotuberculosis

Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague

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