Interaction of Polymorphonuclear Leukocytes with Yersinia enterocolitica: Role of the Yersinia Virulence Plasmid and Modulation by the Iron-Chelator Desferrioxamine B

Ewald, Jann H.; Heesemann, Jürgen; Rüdiger, Harold; Autenrieth, Ingo B.

doi:10.1093/infdis/170.1.140

Cited by 27 publications

(39 citation statements)

References 53 publications

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“…DFO inhibits proliferation of T and B lymphocytes and cytokine production of macrophages and modulates interaction of polymorphonuclear leukocytes with yersiniae (3,21). In keeping with these observations, we and others have demonstrated that DFO increases pathogenicity of Y. enterocolitica in mice, resulting in fatal septicemia and shock (5,39,40).…”

supporting

confidence: 81%

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Schubert

Autenrieth

2000

Clin Diagn Lab Immunol

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The iron chelator desferrioxamine (DFO) B is widely used in the therapy of patients with iron overload. As a side effect, DFO may favor the occurrence of fulminant Yersinia infections. Previous work from our laboratory showed that this might be due to a dual role of DFO: growth promotion of the pathogen and immunosuppression of the host. In this study, we sought to determine whether conjugation of DFO to hydroxyethyl starch (HES-DFO) may prevent exacerbation of Yersinia infection in mice. We found HES-DFO to promote neither growth of Yersinia enterocolitica nor mitogen-induced T-cell proliferation and gamma interferon production by T cells in vitro. Nevertheless, in vivo HES-DFO promoted growth of Y. enterocolitica possibly due to cleavage of HES and release of DFO. The pretreatment of mice with DFO resulted in death of all mice 2 to 5 days after application of a normally sublethal inoculum of Y. enterocolitica, while none of the mice pretreated with HES-DFO died within the first 7 days postinfection. However, some of the HES-DFO-treated mice died 8 to 14 days postinfection. Thus, due to the delayed in vivo effect HES-DFO failed to trigger Yersinia-induced septic shock, which accounts for early mortality in DFO-associated septicemia. Moreover, our data suggest that DFO needs to be taken up by host cells in order to exert its immunosuppressive action. These results strongly suggest that HES-DFO might be a favorable drug with fewer side effects than DFO in terms of DFO-promoted fulminant infections.Yersinia enterocolitica is a gram-negative bacterium which is pathogenic for humans and rodents (23,25). Infection with this pathogen causes a wide range of clinical manifestations including enterocolitis and mesenteric lymphadenitis (28). In immunocompromised patients or patients with iron overload, Yersinia causes systemic infections with abscesses in spleen and liver (27,33,37).Previous work from this laboratory showed that desferrioxamine (DFO) may play a dual role in pathogenesis of Yersinia infection: growth and virulence promotion of Y. enterocolitica by iron provision to the pathogen and immunosuppression of the host. In fact, iron-loaded DFO (ferrioxamine [FO]) can be taken up and used as an iron source by Yersinia (16, 36). The genes encoding FO uptake have been characterized and are considered part of the virulence factors required for high-level pathogenicity of Yersinia (10, 11).On the other hand, DFO exerts effects on various components of the immune system of the host. DFO inhibits proliferation of T and B lymphocytes and cytokine production of macrophages and modulates interaction of polymorphonuclear leukocytes with yersiniae (3, 21). In keeping with these observations, we and others have demonstrated that DFO increases pathogenicity of Y. enterocolitica in mice, resulting in fatal septicemia and shock (5, 39, 40). Moreover, fatal septicemia with Yersinia and other microorganisms including the fungus Rhizopus sp. has been reported for patients undergoing DFO therapy (13,15,40).In an attempt to find drug...

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supporting

confidence: 81%

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Schubert

Autenrieth

2000

Clin Diagn Lab Immunol

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“…The presence of HPI in bacteria using different pathogenic strategies supports the theory that it is not involved in pathogenesis but in increasing fitness by iron acquisition, which is essential for bacteria. Since most HPI-positive bacteria carry additional iron acquisition systems, such as enterochelin in E. coli, with higher affinity to iron, other functions of HPI such as modulation of the cellular host defense by yersiniabactin have been discussed (88,285).…”

Section: Enterohemorrhagic E Colimentioning

confidence: 99%

Pathogenicity Islands in BacterialPathogenesis

2004

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In this review, we focus on a group of mobile genetic elements designated pathogenicity islands (PAI). These elements play a pivotal role in the virulence of bacterial pathogens of humans and are also essential for virulence in pathogens of animals and plants. Characteristic molecular features of PAI of important human pathogens and their role in pathogenesis are described. The availability of a large number of genome sequences of pathogenic bacteria and their benign relatives currently offers a unique opportunity for the identification of novel pathogen-specific genomic islands. However, this knowledge has to be complemented by improved model systems for the analysis of virulence functions of bacterial pathogens. PAI apparently have been acquired during the speciation of pathogens from their nonpathogenic or environmental ancestors. The acquisition of PAI not only is an ancient evolutionary event that led to the appearance of bacterial pathogens on a timescale of millions of years but also may represent a mechanism that contributes to the appearance of new pathogens within a human life span. The acquisition of knowledge about PAI, their structure, their mobility, and the pathogenicity factors they encode not only is helpful in gaining a better understanding of bacterial evolution and interactions of pathogens with eukaryotic host cells but also may have important practical implications such as providing delivery systems for vaccination, tools for cell biology, and tools for the development of new strategies for therapy of bacterial infections

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“…route) were recovered. A piece of each organ was prepared for cryosectioning as previously described (13). Briefly, tissues were embedded in Tissue-Tek O.C.T.…”

Section: Methodsmentioning

confidence: 99%

Expression Analysis of the Yersiniabactin Receptor Gene fyuA and the Heme Receptor hemR of Yersinia enterocolitica In Vitro and In Vivo Using the Reporter Genes for Green Fluorescent Protein and Luciferase

et al. 2001

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The enteropathogenic Yersinia enterocolitica strains have several systems for scavenging iron from their environment. We have studied the expression of the fyuA gene, which encodes the outer membrane receptor for the siderophore yersiniabactin (Ybt), and the hemR gene, which encodes the receptor for heme, using the reporter genes gfp (encoding green fluorescent protein) and luc (encoding firefly luciferase). To study gene expression in vitro as well as in vivo, we have constructed several translational reporter gene fusions to monitor simultaneously expression of fyuA and hemR or expression of one gene by a gfp-luc tandem reporter. Results of the in vitro expression analysis (liquid media) indicated that fyuA and hemR are strongly derepressed under iron starvation conditions, resulting in strong fluorescence and/or luminescence at 27°C. In the in vivo BALB/C mouse infection model, tissue-specific expression of fyuA and hemR reporter fusions was observed. Surprisingly, fyuA and hemR reporter constructs were weakly expressed by yersiniae located in the liver and intestinal lumen, whereas strong expression was found for yersiniae in the peritoneal cavity and moderate expression was found in the spleen. Strikingly, yersiniae carrying fyuA or hemR reporter fusions exhibited threefold-stronger signals when grown in the peritoneal cavity of mice than those growing under iron derepression in vitro. This hyperexpression suggests that besides Fur derepression, additional activators may be involved in the enhanced expression of fyuA and hemR under peritoneal growth conditions. Differential expression of the fyuA and hemR reporter fusions could not be observed, suggesting similar regulation of fyuA and hemR in the mouse infection model.

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Interaction of Polymorphonuclear Leukocytes with Yersinia enterocolitica: Role of the Yersinia Virulence Plasmid and Modulation by the Iron-Chelator Desferrioxamine B

Cited by 27 publications

References 53 publications

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

Pathogenicity Islands in BacterialPathogenesis

Expression Analysis of the Yersiniabactin Receptor Gene fyuA and the Heme Receptor hemR of Yersinia enterocolitica In Vitro and In Vivo Using the Reporter Genes for Green Fluorescent Protein and Luciferase

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