Deferoxamine B but Not Deferoxamine G1 Inhibits Cytokine Production in Murine Bone Marrow Macrophages

Autenrieth, I.B.; Bohn, Erwin; Ewald, Jann H.; Heesemann, Jürgen

doi:10.1093/infdis/172.2.490

Cited by 28 publications

(15 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 82%

See 1 more Smart Citation

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

Schubert

Autenrieth

2000

Clin Diagn Lab Immunol

View full text Add to dashboard Cite

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...

show abstract

supporting

confidence: 82%

“…In an attempt to find drugs with comparable iron binding capacity but reduced Yersinia virulence-enhancing properties, DFO B has been compared with DFO G in terms of its biological properties for bacteria and host cells (3,5). DFO G was found to have fewer immunosuppressive properties and to exert less enhancement of virulence of Yersinia in vivo (5).…”

mentioning

confidence: 99%

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

Schubert

Autenrieth

2000

Clin Diagn Lab Immunol

View full text Add to dashboard Cite

show abstract

“…Furthermore, P. aeruginosa pyochelin is implicated, by virtue of being a catalyst for generating a hydroxyl radical, as a mediator of tissue damage (15). Finally, several different siderophores are capable of directly altering, at least in vitro, the viability and function of cells of the immune system, including T cells and macrophages (2,3,20,47,54,95). Thus, future examination of the role of legiobactin in infection needs to consider the variety of ways that siderophores can act.…”

Section: Discussionmentioning

confidence: 99%

Purification of Legiobactin and Importance of This Siderophore in Lung Infection byLegionella pneumophila

Allard

Dao

Sanjeevaiah³

et al. 2009

Infect Immun

View full text Add to dashboard Cite

When cultured in a low-iron medium, Legionella pneumophila secretes a siderophore (legiobactin) that is both reactive in the chrome azurol S (CAS) assay and capable of stimulating the growth of iron-starved legionellae. Using anion-exchange high-pressure liquid chromatography (HPLC), we purified legiobactin from culture supernatants of a virulent strain of L. pneumophila. In the process, we detected the ferrated form of legiobactin as well as other CAS-reactive substances. Purified legiobactin had a yellow-gold color and absorbed primarily from 220 nm and below. In accordance, nuclear magnetic resonance spectroscopy revealed that legiobactin lacks aromatic carbons, and among the 13 aliphatics present, there were 3 carbonyls. When examined by HPLC, supernatants from L. pneumophila mutants inactivated for lbtA and lbtB completely lacked legiobactin, indicating that the LbtA and LbtB proteins are absolutely required for siderophore activity. Independently derived lbtA mutants, but not a complemented derivative, displayed a reduced ability to infect the lungs of A/J mice after intratracheal inoculation, indicating that legiobactin is required for optimal intrapulmonary survival by L. pneumophila. This defect, however, was not evident when the lbtA mutant and its parental strain were coinoculated into the lung, indicating that legiobactin secreted by the wild type can promote growth of the mutant in trans. Legiobactin mutants grew normally in murine lung macrophages and alveolar epithelial cells, suggesting that legiobactin promotes something other than intracellular infection of resident lung cells. Overall, these data represent the first documentation of a role for siderophore expression in the virulence of L. pneumophila.

show abstract

“…The study of virulence in the mouse infection model with a naturally high-pathogenicity-island-negative Y. enterocolitica of serotype O:9 and O:3 is further complicated by the fact that mice have to be pretreated with desferrioxamine B (DFO) to achieve mouse virulence, and this pretreatment may influence pathogenicity because of the immunosuppressive effect of DFO (4). The virulence of yopQ and yopM (43) mutants in the mouse model was previously studied by using Y. enterocolitica O:9.…”

Section: Discussionmentioning

confidence: 99%

Contribution of the Major Secreted Yops of Yersinia enterocolitica O:8 to Pathogenicity in the Mouse Infection Model

et al. 2004

View full text Add to dashboard Cite

Pathogenic yersiniae (Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica) harbor a 70-kb virulence plasmid (pYV) that encodes a type III secretion system and a set of at least six effector proteins (YopH, YopO, YopP, YopE, YopM, and YopT) that are injected into the host cell cytoplasm. Yops (Yersinia outer proteins) disturb the dynamics of the cytoskeleton, inhibit phagocytosis by macrophages, and downregulate the production of proinflammatory cytokines, which makes it possible for yersiniae to multiply extracellularly in lymphoid tissue. Y. enterocolitica serotype O:8 belongs to the highly mouse-pathogenic group of yersiniae in contrast to Y. enterocolitica serotype O:9. However, there has been no systematic study of the contribution of Yops to the pathogenicity of Y. enterocolitica O:8 in mice. We generated a set of yop gene deletion mutants of Y. enterocolitica O:8 by using the novel Red cloning procedure. We subsequently analyzed the contribution of yopH, -O, -P, -E, -M, -T, and -Q deletions to pathogenicity after oral and intravenous infection of mice. Here we showed for the first time that a ⌬yopT deletion mutant colonizes mouse tissues to a greater extent than the parental strain. The ⌬yopO, ⌬yopP, and ⌬yopE mutants were only slightly attenuated after oral infection since they were still able to colonize the spleen and liver and cause systemic infection. The ⌬yopO mutant was lethal for mice, whereas ⌬yopP and ⌬yopE mutants were successfully eliminated from the spleen and liver 2 weeks after infection. In contrast the ⌬yopH, ⌬yopM, and ⌬yopQ mutants were highly attenuated and not able to colonize the spleen and liver on any of the days tested. The ⌬yopH, ⌬yopO, ⌬yopP, ⌬yopE, ⌬yopM, and ⌬yopQ mutants had only modest defects in the colonization of the small intestine and Peyer's patches. The ⌬yopE mutant was eliminated from the small intestine 3 weeks after infection, whereas the ⌬yopH, ⌬yopP, ⌬yopM, and ⌬yopQ mutants continued to colonize the small intestine at this time.

show abstract

Deferoxamine B but Not Deferoxamine G1 Inhibits Cytokine Production in Murine Bone Marrow Macrophages

Cited by 28 publications

References 32 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

Purification of Legiobactin and Importance of This Siderophore in Lung Infection byLegionella pneumophila

Contribution of the Major Secreted Yops of Yersinia enterocolitica O:8 to Pathogenicity in the Mouse Infection Model

Contact Info

Product

Resources

About