Conjugation of hydroxyethyl starch to desferrioxamine (DFO) modulates the dual role of DFO in Yersinia enterocolitica infection.
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.
Schubert
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Max von Pettenkofer-Institut, Ludwig Maximilians-Universität München, 80336 Munich, Germany.
Autenrieth
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D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D004339:Drug Compounding; D006895:Hydroxyethyl Starch Derivatives / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010952:Plasma Substitutes / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D014774:Virulence; D015009:Yersinia Infections / Q000188:drug therapy* / Q000276:immunology; D015008:Yersinia enterocolitica / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*
D002614:Chelating Agents; D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes; D003676:Deferoxamine