Influence of PhoP and Intra-Species Variations on Virulence of Yersinia pseudotuberculosis during the Natural Oral Infection Route

Pisano, Fabrizio; Heine, Wiebke; Rosenheinrich, Maik; Schweer, Janina; Nuss, Aaron M.; Dersch, Petra

doi:10.1371/journal.pone.0103541

Cited by 15 publications

(11 citation statements)

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“…The pattern of up-regulated inflammatory cytokines/chemokine receptors and strong enrichment of neutrophil-specific transcripts (e.g., stefin A/cystatin A, prokineticin 2, Schlafen 4, Fpr1, and Clec4e) involved in neutrophil mobilization, neutrophil-mediated phagocytosis, and neutrophil extracellular traps formation (24)(25)(26) highlight that the host immune response is dominated by infiltrating neutrophils (Dataset S3). This finding is consistent with previous observations that the number of neutrophils within murine Peyer's patches increases ∼100-fold (14). Among the highest infection-induced immunomodulatory genes were those of the major proinflammatory cytokines (IL-1α, IL-1β, IL-6, IL-17F, and IFN-γ) and the chemokines (CCL2, CXCL1, CXCL2, CXCL3, CXCL5, and CXCL10).…”

Section: Resultssupporting

confidence: 92%

“…The Peyer's patch is the primary replication site of enteropathogenic yersiniae after transcytosis of the intestinal epithelium. Inside the Peyer's patches, the bacteria replicate extracellularly to high numbers (10 7 -10 8 cfu/g tissue) (14). A striking feature of the pathology of an enteric Yersinia infection is inflammation of the intestinal tissue.…”

Section: Resultsmentioning

confidence: 99%

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Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

Nuss

Beckstette

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et al. 2017

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

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Pathogenic bacteria need to rapidly adjust their virulence and fitness program to prevent eradication by the host. So far, underlying adaptation processes that drive pathogenesis have mostly been studied in vitro, neglecting the true complexity of host-induced stimuli acting on the invading pathogen. In this study, we developed an unbiased experimental approach that allows simultaneous monitoring of genome-wide infection-linked transcriptional alterations of the host and colonizing extracellular pathogens. Using this tool for Yersinia pseudotuberculosis-infected lymphatic tissues, we revealed numerous alterations of host transcripts associated with inflammatory and acute-phase responses, coagulative activities, and transition metal ion sequestration, highlighting that the immune response is dominated by infiltrating neutrophils and elicits a mixed T H 17/T H 1 response. In consequence, the pathogen's response is mainly directed to prevent phagocytic attacks. Yersinia up-regulates the gene and expression dose of the antiphagocytic type III secretion system (T3SS) and induces functions counteracting neutrophil-induced ion deprivation, radical stress, and nutritional restraints. Several conserved bacterial riboregulators were identified that impacted this response. The strongest influence on virulence was found for the loss of the carbon storage regulator (Csr) system, which is shown to be essential for the up-regulation of the T3SS on host cell contact. In summary, our established approach provides a powerful tool for the discovery of infection-specific stimuli, induced host and pathogen responses, and underlying regulatory processes.tissue dual RNA-seq | host-pathogen interaction | host-adapted metabolism | noncoding RNAs | Yersinia

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

Nuss

Beckstette

Пименова

et al. 2017

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

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137

117

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“…One significant difference between these strains is that YPIII is known to carry a mutation that renders PhoP nonfunctional. PhoP is important for intercellular survival, and it is likely that a lack of a functional PhoP could at least in part affect the ability of YPIII to efficiently colonize PPs and MLNs (51,52). We have also observed a similar colonization defect in PPs and MLNs in mice infected with a ΔtatC mutant of the YPIII strain (U. Avican, unpublished results).…”

Section: Discussionmentioning

confidence: 64%

The Tat Substrate SufI Is Critical for the Ability of Yersinia pseudotuberculosis To Cause Systemic Infection

et al. 2017

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The twin arginine translocation (Tat) system targets folded proteins across the inner membrane and is crucial for virulence in many important humanpathogenic bacteria. Tat has been shown to be required for the virulence of Yersinia pseudotuberculosis, and we recently showed that the system is critical for different virulence-related stress responses as well as for iron uptake. In this study, we wanted to address the role of the Tat substrates in in vivo virulence. Therefore, 22 genes encoding potential Tat substrates were mutated, and each mutant was evaluated in a competitive oral infection of mice. Interestingly, a ΔsufI mutant was essentially as attenuated for virulence as the Tat-deficient strain. We also verified that SufI was Tat dependent for membrane/periplasmic localization in Y. pseudotuberculosis. In vivo bioluminescent imaging of orally infected mice revealed that both the ΔsufI and ΔtatC mutants were able to colonize the cecum and Peyer's patches (PPs) and could spread to the mesenteric lymph nodes (MLNs). Importantly, at this point, neither the ΔtatC mutant nor the ΔsufI mutant was able to spread systemically, and they were gradually cleared. Immunostaining of MLNs revealed that both the ΔtatC and ΔsufI mutants were unable to spread from the initial infection foci and appeared to be contained by neutrophils, while wild-type bacteria readily spread to establish multiple foci from day 3 postinfection. Our results show that SufI alone is required for the establishment of systemic infection and is the major cause of the attenuation of the ΔtatC mutant.KEYWORDS Yersinia pseudotuberculosis, Tat pathway, virulence, SufI, mesenteric lymph nodes, neutrophils T he genus Yersinia includes three species that are pathogenic to humans: Yersinia pestis, the causative agent of plague, and the two enteropathogens Y. enterocolitica and Y. pseudotuberculosis, which normally cause a self-limiting disease with symptoms ranging from mild diarrhea, enterocolitis, septicemia, and mesenteric lymphadenitis to reactive arthritis in humans after ingestion of contaminated food or water (1). Once it is ingested, Y. pseudotuberculosis traverses the epithelial barrier through M cells and infects the associated lymphoid tissues, such as Peyer's patches (PPs) and cecal patches, and later spreads to the mesenteric lymph nodes (MLNs). Although the infection is usually self-limited in humans, the infection caused by the two enteropathogenic Yersinia species in mice readily progresses to become systemic and disseminates to the spleen and liver (2). The main virulence arsenal of Yersinia is the type III secretion system (T3SS), which is encoded by an ϳ70-kb virulence plasmid. The T3SS enables the translocation of virulence effector proteins directly into the cytosol of the target host cell, which results in the disruption of host signaling and early immune

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“…It was previously shown by our group that upon infection with Y . pseudotuberculosis YPIII, NK cell numbers in PPs and mLNs increased while a decrease of NK cells occurred in the spleen and blood [ 23 , 24 ]. In order to evaluate the overall impact of NK cells during Y .…”

Section: Resultsmentioning

confidence: 99%

Natural Killer Cells Mediate Protection against Yersinia pseudotuberculosis in the Mesenteric Lymph Nodes

et al. 2015

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Natural killer cells play a crucial role in the initial defense against bacterial pathogens. The crosstalk between host cells infected with intracellular pathogens and NK cells has been studied intensively, but not much attention has been given to characterize the role of NK cells in the response to extracellular bacterial pathogens such as yersiniae. In this study we used antibody-mediated NK cell depletion to address the importance of this immune cell type in controlling a Y. pseudotuberculosis infection. Analysis of the bacterial counts was used to follow the infection and flow cytometry was performed to characterize the composition and dynamic of immune cells. Depletion of NK cells led to higher bacterial loads within the mesenteric lymph nodes. We further show that in particular CD11b+ CD27+ NK cells which express higher levels of the activation marker CD69 increase within the mesenteric lymph nodes during a Y. pseudotuberculosis infection. Moreover, in response to the activation NK cells secrete higher levels of IFNy, which in turn triggers the production of the proinflammatory cytokine TNFα. These results suggest, that NK cells aid in the clearance of Y. pseudotuberculosis infections mainly by triggering the expression of proinflammatory cytokines manipulating the host immune response.

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Influence of PhoP and Intra-Species Variations on Virulence of Yersinia pseudotuberculosis during the Natural Oral Infection Route

Cited by 15 publications

References 54 publications

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

The Tat Substrate SufI Is Critical for the Ability of Yersinia pseudotuberculosis To Cause Systemic Infection

Natural Killer Cells Mediate Protection against Yersinia pseudotuberculosis in the Mesenteric Lymph Nodes

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