Role of Iron in Bacterial Infection

Bullen, J. J.; Rogers, H. J.; Griffiths, Elwyn

doi:10.1007/978-3-642-66956-9_1

Cited by 364 publications

(326 citation statements)

References 139 publications

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“…The highest level of transferrin is in serum, and that of lactoferrin within polymorphonuclear leucocytes and in mucosal fluids (Masson et al, 1966(Masson et al, , 1969. They have protean effects on micro-organisms ; variably acting as growth factors, inducing iron uptake systems, and for selected bacteria producing bacteriostasis (Bullen, 198 1 ;Bullen et al, 1978;Griffiths, 1975;Norrod & Williams, 1978). It has been suggested that this last effect contributes to antibacterial host defence, and that the mechanism of bacteriostasis is sequestration of environmental iron causing nutritional deprivation of susceptible organisms (Finkelstein et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

“…While this could be due to further iron deprivation through anti-siderophore antibodies, enhancing antibodies have been found to be directed against lipopolysaccharide (LPS) 0-antigens (Finkelstein et al, 1983;Stephens et al, 1980). Similarly, transferrin contributes to antibody-and complementmediated serum antibacterial activity towards several Gram-negative species, although the mechanism of action is not known (Bullen et al, 1978;Griffiths, 1975;Norrod & Williams, 1978;Fitzgerald & Rogers, 1980). Finally, other work indicates that lactoferrin may directly kill selected bacterial strains through an undefined mechanism (Arnold et al, 1977(Arnold et al, , 1982Bortner et al, 1986;Kalmar & Arnold, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…Gramnegative bacteria have an outer membrane composed of an asymmetric lipid bilayer with large LPS molecules restricted to the outer leaflet (Leive, 1974;Nikaido & Vaara, 1985). The LPS molecules are anionic and are stabilized within the membrane by associated cations, primarily Ca2+ and Mg2+ (Coughlin et al, 1983). By binding membrane-stabilizing cations, EDTA releases LPS from the outer membrane, concurrently increasing membrane permeability to hydrophobic molecules and sensitizing bacteria to membrane-active agents (Leive, .…”

Section: Introductionmentioning

confidence: 99%

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Lactoferrin and transferrin damage of the Gram-negative outer membrane is modulated by Ca2+ and Mg2+

Ellison¹,

LaForce²,

Giehl³

et al. 1990

Journal of General Microbiology

109

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Lactoferrin and transferrin have antimicrobial activity against selected Gram-negative bacteria, but the mechanism of action has not been defined. We studied the ability of lactoferrin and transferrin to damage the Gram-negative outer membrane. Lipopolysaccharide release by the proteins could be blocked by concurrent addition of Ca2+ and Mg2+. Addition of Ca2+ also blocked the ability of lactofenin to increase the susceptibility of Escherichia coli to rifampicin. Transferrin, but not lactoferrin, increased susceptibility of Gram-negative bacteria to deoxycholate, with reversal of sensitivity occurring with exposure to Ca2+ or Mg2+. In transmission electron microscopy studies polymyxin B caused finger-like membrane projections, but no morphological alterations were seen in cells exposed to EDTA, lactoferrin or transferrin. These data provide further evidence that lactoferrin and transferrin act as membrane-active agents with the effects modulated by Ca2+ and Mg2+.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lactoferrin and transferrin damage of the Gram-negative outer membrane is modulated by Ca2+ and Mg2+

Ellison¹,

LaForce²,

Giehl³

et al. 1990

Journal of General Microbiology

109

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“…The future tance of iron in infections caused by bacteria, fungi, and of therapy of chronic hepatitis C will likely include measures other potential pathogens. [1][2][3] In addition, patients with iron to decrease oxidative stress and injury and multidrug combi-overload, attributable either to genetic (primary) or secondnations, including inhibitors of the hepatitis C viral protease ary forms of hemochromatosis are known to be at increased and RNA polymerase. (HEPATOLOGY 1997;26(Suppl 1):143S-risk for development of severe infections by such organisms.…”

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confidence: 99%

Therapy of hepatitis C: Other options

Bonkovsky¹

1997

Hepatology

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Because current standard therapy of chronic hepatitis C ultimate therapeutic goal continues to be eradication of all detectable virus in the blood, liver, or other organs. However, with alpha interferon is less than ideal, numerous other approaches have been studied. Iron in the liver, particularly that because of the ability of hepatitis C virus (HCV) to mutate rapidly and become resistant to antiviral agents and immune found in vascular endothelial cells of portal tracts, has been associated with decreased responsiveness to alpha interferon surveillance, the value of achieving other, lesser therapeutic goals should not be minimized. Such goals might include therapy. Iron reduction alone, generally achieved by therapeutic phlebotomy, regularly has been associated with biochemi-the following: (1) diminution of levels of virus in the blood and risk of infectivity; (2) diminution in the severity of hecal improvement (decrease in serum alanine aminotransferase), but not with virological improvement. Iron reduction patic inflammation and necrosis; (3) diminution in the rate of progression of hepatic fibrosis and development of cirrhohas been reported to increase the therapeutic response to alpha interferon. Most studies of this combination have been sis; and (4) prevention or delay in development of complications of cirrhosis, particularly hepatocellular carcinoma. conducted in patients who had not responded to interferon alone; in these patients, improved responsiveness has beenThe eventual conquest of HCV infection will depend on development of an effective vaccine. Even when that goal observed in some, but not all studies. In patients not previously treated, iron reduction was found in a recent trial to has been reached, many patients will remain who are already chronically infected with the virus. Accordingly, approaches improve the sustained biochemical and virological response rate from 5% to 29%. Hepatic iron and chronic hepatitis C to management of chronic hepatitis C, beyond the use of interferons, with or without ribavirin, are worthy of considerincrease oxidative stress in the liver and are associated with decreases in hepatic glutathione levels. In one report, adminis-ation. This review summarizes the current status of other approaches to therapy of chronic hepatitis C (Table 1). tration of N-acetyl cysteine, a sulfhydryl donor, led to improved response to interferon in chronic hepatitis C. Several IRON REDUCTION cytokines and immunomodulators have undergone limited study; perhaps the most promising of these is thymosin a-1. Role of Iron in Infectious DiseasesIn one small study, amantadine was found to produce some It has been recognized for many years that iron is an eleresponse in patients who previously had failed to respond to ment essential to the replication of virtually all organisms, interferon. Ursodiol improves serum aminotransferase levels including virulent microorganisms. Many clinical observain chronic hepatitis C but has no antiviral effect, nor has it tions and experimental studies have e...

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“…Presumably for this reason and to limit its availability to pathogenic microorganisms, Fe acquisition, transport, and storage are tightly regulated. In vivo, free extracellular Fe is kept to a minimum (2). The vast majority of extracellular Fe is chelated to one of two related proteins, transferrin and lactoferrin.…”

mentioning

confidence: 99%

Multivalent Metal-Induced Iron Acquisition from Transferrin and Lactoferrin by Myeloid Cells

Olakanmi

Rasmussen

Lewis

et al. 2002

The Journal of Immunology

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We previously described a unique, high-capacity, ATP-independent mechanism through which myeloid cells acquire Fe from low-m.w. chelates. The rate of this Fe acquisition is markedly increased by cellular exposure to multivalent metal cations. Because most Fe in vivo is bound to transferrin or lactoferrin, we examined whether this mechanism also contributes to myeloid cell acquisition of Fe from transferrin and/or lactoferrin. Using HL-60 cells as a model system, we show cellular acquisition of 59Fe from both lactoferrin and transferrin that was unaffected by conditions that depleted the cells of ATP or disrupted their cytoskeleton. Fe acquisition was dramatically increased by cell exposure to various metals including Ga3+, Gd3+, Al3+, Fe3+, La3+, Zr4+, Sn4+, Cu2+, and Zn2+ by a process that was reversible. Exposure to these same metals also increased binding of both transferrin and lactoferrin to the cell surface by a process that does not appear to involve the well-described plasma membrane receptor for transferrin. Approximately 60% of the Fe acquired by the cells from transferrin and lactoferrin remained cell associated 18 h later. HL-60 cells possess a high-capacity multivalent metal-inducible mechanism for Fe acquisition from transferrin and lactoferrin that bears many similarities to the process previously described that allows these and other cell types to acquire Fe from low-m.w. Fe chelates. The biologic importance of this mechanism may relate to its high Fe acquisition capacity and the speed with which it is able to rapidly adapt to the level of extracellular Fe.

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Role of Iron in Bacterial Infection

Cited by 364 publications

References 139 publications

Lactoferrin and transferrin damage of the Gram-negative outer membrane is modulated by Ca2+ and Mg2+

Lactoferrin and transferrin damage of the Gram-negative outer membrane is modulated by Ca2+ and Mg2+

Therapy of hepatitis C: Other options

Multivalent Metal-Induced Iron Acquisition from Transferrin and Lactoferrin by Myeloid Cells

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