Military Strategies for Sustainment of Nutrition and Immune Function in the Field (1999) / Chapter Skim
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15 Iron Metabolism, Microbial Virulence, and Host Defenses
15 Iron Metabolism, Microbial Virulence, and Host Defenses
Pages 317-336
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From page 317... ...
. Iron Beta Cam Also ~ Virulence, Ad Host Defenses ~ j.
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From page 318... ...
Mammals have overcome the environmental restrictions and biological imperatives of bound, insoluble iron by developing an effective iron acquisition system able to compete with hydroxyl ion for ferric iron. Iron absorption, transport to and into cells, and storage are closely regulated by systems that sense the amount of available free iron and rapidly respond to maintain iron homeostasis.
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From page 319... ...
A major function of irontransferrin is to provide a continuous source of iron for the rapid enzyme turnover, such as demonstrated by DNA synthesis, because the rate limiting enzyme for the production of nucleotides, ribonucleotide reductase is required for DNA synthesis. Uptake of iron from transferrin to the cell follows the binding of iron-transferrin to the transferrin receptor (TfR)
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From page 320... ...
Under conditions of restricted iron availability, when a pathogen enters a human, the microbe rapidly and coordinately derepresses a set of genes responsible for the synthesis of iron acquisition and transport proteins that constitutes a system of iron chelators, outer membrane iron-siderophore receptors, and periplasmic and inner membrane transport proteins. This system is complex, involves multiple structural and regulatory genes and proteins, uses iron concentration as the signal, and is highly efficient (Neilands, 1995~.
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From page 321... ...
In fact, the methane sulfonate salt of deferrated ferrioxamine B is used clinically as an iron chelator drug, Desferal, to treat iron overload states. Finally, when the iron-siderophore complex reaches the cytoplasm, iron is released from ferric enterochelin by an esterase or from aerobactin or citrate siderophores by reduction mediated through Gavin reductases (ferri-siderophore reductase)
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From page 322... ...
The clear evidence that pathogens adapt to low iron availability, that they have developed intricate iron acquisition mechanisms, and that they use iron levels as the signal for transcriptional regulation of these systems raises doubt about the validity of the iron-withholding hypothesis of nutritional immunity (Kontoghiorghies and Weinberg, 1995~. Given the existence of these ~ronregulated systems for iron acquisition, it may be reasonable to believe that iron deficiency or acute phase shifts of iron Tom the circulation to ~nhacellular storage sites during infection will restrict microbial acquisition of iron in vivo.
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From page 323... ...
In fact, iron uptake must precede DNA synthesis (Kronke et al., 1985) , and therefore, transferrin receptors (CD71)
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From page 324... ...
Neutrophil myeloperoxidase, an iron metalloenzyme that generates reactive bactericidal halides during PMN phagocytosis, is reduced in iron deficiency states (Prasad, 1979; Turgeon-O'Brien et al., 1985; Yetgin et al., 1979~. Myeloperoxidase-mediated killing is a redundant system; however, iron is also required for the production by phagocytic cells of reactive microbicidal oxygen species via the Fenton reaction (Fridovich, 1978~.
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From page 325... ...
Similarly, the enhanced susceptibility to infection in sickle-cell patients occurs primarily in the young, before significant iron overload occurs. Clinical analysis thus suggests that it is not increased free iron availability in iron overload that is associated with increased incidence or severity of infection.
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From page 326... ...
Nonetheless, there are a few examples where the association of iron overload and susceptibility to infection is related to the increased free iron available for the growth of pathogens that do not compete well for proteinbound iron in vivo. For example, low virulence Yersinia enterocolitica, which
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From page 327... ...
, and infections are documented in iron overload patients (Blake et al., 1979~. Other, less common associations between chelation therapy and sepsis include Listeria (Mossey and Sondheimer, 1985)
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From page 328... ...
These data demonstrate that excess free iron may have a direct enhancing effect on a limited number of pathogens and that chronic iron overload results in oxidative and peroxidative damage to the immune system and impairs its function. The effects of iron overload cannot therefore be considered to be a continuum ranging from protection of the host due to iron withholding at one end to increased susceptibility due to iron excess at the other, as the nutritional immunity hypothesis presumes.
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From page 329... ...
1986. Decreased natural killer activity in thalassemia major: A possible consequence of iron overload.
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1987. Neutrophil dysfunctions in thalassemia major: The role of iron overload.
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1987. Mucormycosis a new risk of deferrioxamine therapy in dialysis patients with aluminum or iron overload?
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1977. Effects of iron chelators and iron overload on Salmonella infection.
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1985. Listeriosis in patients with long-term hemodialysis and transfusional iron overload.
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1992. Receptor-mediated iron uptake and intracellular iron transport.
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1991. Role of iron in T-cell activation: Thl clones differ from Th2 clones in their sensitivity to inhibition of DNA synthesis caused by IgG Mabs against the transferrin receptor and the iron chelator desferoxamine.
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From page 336... ...
Is there any expectation of gram positives to have an iron uptake system because the membranes would conserve it differently? GERALD KEUSCH: There are parallels in the gram positives.
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