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The Role of Iron and Hepcidin in Infection
Başlık:
The Role of Iron and Hepcidin in Infection
Yazar:
Stefanova, Debora Chavdarova, author.
ISBN:
9780355939941
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (160 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Tomas Ganz; Elizabeta Nemeth Committee members: James Tidball; Otto Yang.
Özet:
Iron is an essential trace nutrient for both higher organisms and bacteria. Consequently, hosts have evolved to sequester iron during infection, while pathogens have developed multiple iron acquisition systems to access iron pools in the host. Hepcidin, the master iron-regulatory hormone, is induced by inflammatory cytokines early during infections. Hepcidin lowers extracellular iron concentration by binding to and inhibiting the cellular iron exporter ferroportin. Using structural modeling and site-directed mutagenesis, we analyzed the structural basis of ferroportin interaction with hepcidin.
Hepcidin induction by inflammation causes a rapid decrease in plasma iron concentration (hypoferremia) accompanied by iron retention within target cells (macrophages, enterocytes, hepatocytes). This response to infection is highly conserved during vertebrate evolution. In the main part of this thesis, we show that hepcidin is essential for protection against extracellular Gram-negative bacterium Yersinia enterocolitica. At the same inocula, hepcidin-deficient mice suffer 100% mortality while WT mice survive disease-free. We determine that it is the spontaneous iron overload of hepcidin-deficient mice that promotes susceptibility to infection. We find that hepcidin is not universally protective and plays no role in catheter-associated Staphylococcus aureus infection or in macrophage-tropic Mycobacterium tuberculosis. Surprisingly, infection with clinical isolates of Escherichia coli, which was not previously considered siderophilic, caused sepsis and 60% to 100% mortality in hepcidin deficiency and iron overload while WT mice suffered 0% mortality. Although the difference in survival was not as pronounced, similar results were obtained with another clinically common non-siderophilic pathogen: Klebsiella pneumoniae..
Furthermore, we found that the cause of increased susceptibility of hepcidin-deficient mice to certain Gram-negative pathogens (Y. enterocolitica, K. pneumoniae, E. coli) is the appearance in plasma of non-transferrin bound iron (NTBI), an iron species that stimulates the growth of these gram-negative bacteria. Endogenous hepcidin in wild-type mice or therapeutic administration of the hepcidin agonist minihepcidin to hepcidin-deficient mice eliminate NTBI and thus protect from infection-associated mortality in all 3 infection models.
We hypothesize that in future studies many more pathogens will manifest iron-dependent pathogenicity. With antibiotic resistance rising rapidly, understanding the role of iron and hepcidin in host defense can provide new tools for combating infections.
Notlar:
School code: 0031
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680633.1) | 680633-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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