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Query: UMLS:C0023241 (Legionella)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Legionella pneumophila is a facultative intracellular parasite of alveolar macrophages. In vitro studies have shown that lymphokine-activated mononuclear phagocytes inhibit intracellular replication of L. pneumophila. To determine if recovery from legionellosis is associated with activation of alveolar macrophages in vivo to resist L. pneumophila, we studied an animal model of Legionnaires' disease. Rats were exposed to aerosolized L. pneumophila and alveolar macrophages were harvested during the recovery phase of infection. We compared these alveolar exudate macrophages with normal resident alveolar macrophages for the capacity to support or inhibit the intracellular growth of L. pneumophila. We also measured Ia expression as a marker of immunologic activation, and studied binding of bacteria, superoxide release, and the expression of transferrin receptors as potential mechanisms of resistance to L. pneumophila. For perspective on the specificity of these responses, we also studied alveolar exudate cells elicited by inhalation of heat-killed L. pneumophila, live Listeria monocytogenes, and live Escherichia coli. We found that alveolar exudate macrophages elicited by live L. pneumophila, but not heat-killed L. pneumophila, resisted the intracellular growth of L. pneumophila. Exudate macrophages in resolving legionellosis exhibited increased Ia expression, diminished superoxide production, and downregulation of transferrin receptors. Binding of L. pneumophila to exudate macrophages was indistinguishable from that to resident macrophages in the presence of normal serum, and augmented in the presence of immune serum. Alveolar exudate macrophages elicited by E. coli also inhibited growth of L. pneumophila, and exhibited a modest increase in Ia expression without change in transferrin receptors. Exudate cells induced by L. monocytogenes exhibited up-regulation of Ia without diminution of superoxide release. Alveolar cells harvested after inhalation of heat-killed L. pneumophila did not differ from resident alveolar macrophages in the expression of surface markers. These findings suggest that alveolar macrophages are immunologically activated in vivo to serve as effector cells in resolving legionellosis, and that live bacteria are required to induce this expression of immunity. The mechanism of resistance to parasitism by L. pneumophila may entail restriction of the intracellular availability of iron, but does not involve diminished bacterial binding or an augmented respiratory burst.
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PMID:Alveolar macrophage activation in experimental legionellosis. 164 46

The growth inhibiting activity of transferrins, citrate, 2-2' dipyridyl and desferrioxamine methanesulphonate towards Legionella spp. and their serogroups was investigated. The inhibitory activity of all these compounds depended upon the iron-free state of the molecules and was abolished by saturation with iron. No bactericidal effect by transferrins was observed at concentrations up to four times the minimal bacteriostatic concentration. No interaction of transferrins with the legionella cell surface was detected by direct or indirect fluorescence assay, or by dialysis culture experiments in which transferrin was separated from the bacterial cells. The demonstration of a siderophore-like activity in supernates of iron-deficient legionella cultures may account for the ability of Legionella spp. to multiply in conditions of iron restriction.
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PMID:Growth of Legionella spp. under conditions of iron restriction. 182 50

Legionella pneumophila has been shown to survive and multiply in a variety of intracellular environments, including protozoa and human mononuclear phagocytes. However, the mechanism by which this organism acquires iron in the intracellular environment has not been studied. Since L. pneumophila does not produce siderophores, alternative methods of iron acquisition were investigated. Virulent strains of L. pneumophila were able to grow in media containing as little as 3 microM iron, whereas avirulent cells required a minimum of 13 microM iron for growth. Neither virulent nor avirulent cells were able to utilize 55Fe bound to transferrin. When incubated in the presence of 55Fe in the form of ferric chloride, both virulent and avirulent cells accumulated equal amounts of iron. The uptake of iron was energy dependent as indicated by inhibition of 55Fe uptake at 4 degrees C and preincubation of the cells with KCN. Treatment of virulent cells with pronase or trypsin had no effect on iron uptake. In contrast, pronase or trypsin treatment of avirulent cells resulted in increased uptake of iron. Iron reductase activity in both virulent and avirulent cells was demonstrated, with the highest specific activity associated with the periplasmic fraction. Maximum reductase activity of virulent cells occurred with NADH as the reductant. In contrast, avirulent cells showed a twofold increase in enzyme activity when NADPH was used as the reductant. These results suggest that an iron reductase is important in iron acquisition by L. pneumophila.
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PMID:Acquisition of iron by Legionella pneumophila: role of iron reductase. 190 41

We have been exploring the role of iron in the pathogenesis of the intracellular bacterial pathogen Legionella pneumophila. In previous studies, we have demonstrated that L. pneumophila intracellular multiplication in human monocytes is iron dependent and that IFN gamma-activated monocytes inhibit L. pneumophila intracellular multiplication by limiting the availability of iron. In this study, we have investigated the effect on L. pneumophila intracellular multiplication of lactoferrin, an iron-binding protein which is internalized via specific receptors on monocytes, and of nonphysiologic iron chelates which enter monocytes by a receptor-independent route. Apolactoferrin completely inhibited L. pneumophila multiplication in nonactivated monocytes, and enhanced the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication. In contrast, iron-saturated lactoferrin had no effect on the already rapid rate of L. pneumophila multiplication in nonactivated monocytes. Moreover, it reversed the capacity of activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron from the lactoferrin-lactoferrin receptor pathway. The capacity of iron-lactoferrin to reverse monocyte activation was dependent upon its percent iron saturation and not just its total iron content. Similarly, the nonphysiologic iron chelates ferric nitrilotriacetate and ferric ammonium citrate completely reverse and ferric pyrophosphate partially reversed the capacity of IFN gamma-activated monocytes to inhibit L. pneumophila intracellular multiplication, demonstrating that L. pneumophila can utilize iron derived from nonphysiologic iron chelates internalized by monocytes independently of the transferrin and lactoferrin endocytic pathways. This study suggests that at sites of inflammation, lactoferrin may inhibit or promote L. pneumophila intracellular multiplication in mononuclear phagocytes depending upon its degree of iron saturation. In addition, this study suggests a potential role for PMN in host defense against L. pneumophila--providing apolactoferrin to infected monocytes--and it supports the concept that PMN and monocytes may cooperate in host defense against intracellular parasites and other pathogens.
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PMID:Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila. 191 66

Chloroquine and ammonium chloride, by virtue of their basic properties, have been shown to raise endocytic and lysosomal pH and thereby interfere with normal iron metabolism in a variety of cell types, including mononuclear phagocytes. Cellular iron metabolism is of critical importance to Legionella pneumophila, an intracellular bacterial pathogen whose capacity to multiply in human mononuclear phagocytes is dependent upon the availability of intracellular iron. In view of this, we have studied the effects of chloroquine and ammonium chloride on L. pneumophila intracellular multiplication in human monocytes. Chloroquine, at a concentration of 20 microM, and ammonium chloride, at a concentration of 20 mM, inhibited L. pneumophila intracellular multiplication by 1.4 +/- 0.2 (SEM) logs and 1.5 +/- 0.2 logs, respectively. Chloroquine- and ammonium chloride-induced inhibition of L. pneumophila intracellular multiplication was completely reversed by iron nitrilotriacetate, an iron compound which is soluble in the neutral to alkaline pH range, but not by iron transferrin, which depends upon acidic intracellular conditions to release iron. Chloroquine had no major direct effect on L. pneumophila multiplication in artificial media except at extremely high concentrations (15,000-fold that which inhibited L. pneumophila multiplication in mononuclear phagocytes), and inhibition at such concentrations was not reversed by iron nitrilotriacetate. This study demonstrates that chloroquine and ammonium chloride inhibit the intracellular multiplication of L. pneumophila by limiting the availability of iron to the bacterium. It is possible that such a mechanism of action underlies chloroquine's antimicrobial effect against other intracellular pathogens, such as the agents of malaria and tuberculosis.
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PMID:Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. 205 29

We have investigated the role of iron in the intracellular biology of Legionella pneumophila in human monocytes and in the effector arm of cell-mediated immune defense against this intracellular bacterial pathogen. To determine if L. pneumophila intracellular multiplication is iron dependent, we studied the effect of the iron chelator deferoxamine on L. pneumophila infection of monocytes. Deferoxamine at 15 microM completely inhibited L. pneumophila intracellular multiplication. The inhibitory effect of deferoxamine was reversed with equimolar iron-saturated transferrin but not apotransferrin. To examine the potential role of iron in monocyte activation, we investigated the influence of iron-saturated transferrin on L. pneumophila multiplication in IFN gamma-activated monocytes. Iron transferrin, but not apotransferrin, neutralized the capacity of activated monocytes to inhibit L. pneumophila multiplication. To explore a potential mechanism by which activated monocytes might limit the availability of intracellular iron, we examined transferrin receptor expression on nonactivated and activated monocytes cultured in vitro for 5 d. By fluorescence-activated flow cytometry, activated monocytes exhibited markedly fewer transferrin receptors than nonactivated monocytes. By Scatchard analysis of 125I-transferrin binding to monocytes, nonactivated monocytes had 38,300 +/- 12,700 (mean +/- SE) transferrin binding sites, whereas activated monocytes had 10,300 +/- 1,600, a reduction of 73%. Activated and nonactivated monocytes had a similar mean Kd (1.8 +/- 0.2 nM). This study demonstrates that (a) L. pneumophila intracellular multiplication is iron dependent; (b) activated monocytes inhibit L. pneumophila multiplication by limiting the availability of intracellular iron; and (c) transferrin receptors are downregulated on IFN gamma-activated monocytes.
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PMID:Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. 249 41

Guinea pigs were infected with either 5 or 100 cfu of Legionella pneumophila by aerosol exposure. Between two and 10 days after infection, groups of animals were killed, and their lungs and spleen were removed and cultured quantitatively. L. pneumophila multiplied in the lungs and spread to the spleen; the organisms were cleared first from the spleen and then the lungs. Significant changes were demonstrated in serum iron and transferrin levels and body temperature. The body temperature correlated directly and the serum iron concentration correlated inversely with the number of L. pneumophila recovered from the lungs but not from the spleen. These data suggest that fever and iron may restrict the growth of L. pneumophila in vivo.
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PMID:Changes in iron and transferrin levels and body temperature in experimental airborne legionellosis. 682 46

Legionella pneumophila, a facultative intracellular pathogen, replicates within and kills thioglycolate-elicited (TG) macrophages from A/J mice, while growth is inhibited in TG macrophages from BALB/c mice which show no impaired viability. The role of iron in BALB/c and A/J macrophages regarding their permissiveness to L. pneumophila intracellular growth was investigated. We previously reported that TG macrophages from the A/J mouse strain readily supported the intracellular growth of L. pneumophila, while resident macrophages from the same strain of mice were not permissive. Recently we also found that such a difference in permissiveness between both A/J macrophage populations may be explained, at least in part, to intracellular availability of iron. In this report, differences in permissiveness to L. pneumophila growth between A/J TG macrophages and BALB/c TG macrophages was not due to intracellular iron availability. BALB/c and A/J TG macrophages exhibited similar expression of transferrin receptor and cellular iron content. The treatment of BALB/c TG macrophages with different iron compounds, namely ferric nitrilotriacetate (12.5-100 microM), ferric citrate (12.5-100 microM) and transferrin (0.5-5 mg ml-1), did not stimulate the intracellular proliferation of L. pneumophila. The reduction of intracellular iron availability by treatment with antibodies against transferrin receptor or with desferrioxamine suppressed the growth of L. pneumophila within BALB/c TG macrophages, suggesting that these cells do not restrict L. pneumophila growth because of iron. The production of nitric oxide was also similar in both macrophage populations, as measured by the Griess reaction. However, the synthesis of oxygen reactive species was three times higher in non-permissive BALB/c macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differences and similarities in permissive A/J versus non-permissive BALB/c murine macrophages infected with Legionella pneumophila: the role of iron. 792 Apr 66

A/J mouse macrophages infected with Legionella pneumophila and treated with gamma interferon (IFN-gamma) in vitro developed potent antimicrobial activity. This antilegionella activity was independent of the macrophage capacity to generate reactive oxygen intermediates, since the oxygen radical scavengers catalase, superoxide dismutase, mannitol, and thiourea had no effect on the antilegionella activity of IFN-gamma-activated macrophages. Likewise, whereas the ability of IFN-gamma-activated macrophages to synthesize reactive nitrogen intermediates was markedly inhibited by the L-arginine (Arg) analogs, NG-monomethyl-L-arginine and L-aminoguanidine, as well as by incubation in L-Arg-free medium, their ability to inhibit the intracellular growth of L. pneumophila remained intact. The intracellular growth of L. pneumophila in A/J macrophages was inhibited by the iron(III) chelator desferrioxamine and reversed by Fe-transferrin as well as by ferric salts. Additionally, IFN-gamma-activated macrophages incorporated 28% less 59Fe(III) compared with nonactivated cells. Nonetheless, only partial blocking of growth restriction was observed when IFN-gamma-stimulated macrophages were saturated with iron(III). Indole-propionic acid, which appears to inhibit the biosynthesis of L-tryptophan (L-Trp), was an L-Trp-reversible growth inhibitor of L. pneumophila in macrophages, implying that the intracellular replication of this pathogen is also L-Trp dependent. However, an excess of exogenous L-Trp did not reverse the growth inhibition due to IFN-gamma, though a small synergistic effect was observed when the culture medium was supplemented with both iron(III) and L-Trp. We conclude that IFN-gamma-activated macrophages inhibit the intracellular proliferation of L. pneumophila by reactive oxygen intermediate- and reactive nitrogen intermediate-independent mechanisms and just partially by nutritionally dependent mechanisms. We also suggest that additional mechanisms, still unclear, may be involved, since complete reversion was never obtained and since at higher concentrations of IFN-gamma, iron(III) did not induce any significant reversion in the L. pneumophila growth inhibition.
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PMID:Inhibition of Legionella pneumophila growth by gamma interferon in permissive A/J mouse macrophages: role of reactive oxygen species, nitric oxide, tryptophan, and iron(III). 803 89

We have investigated the modulation of iron in two populations of macrophages which differ in susceptibility to Legionella pneumophila intracellular proliferation. Previously, we reported that thioglycolate-elicited peritoneal macrophages obtained from the inbred A/J mouse strain readily support the intracellular growth of L. pneumophila, while resident macrophages from the same strain do not. In this study, we show that A/J elicited macrophages exhibit markedly higher expression of transferrin receptor and intracellular iron content than A/J resident macrophages. Furthermore, apotransferrin and desferrioxamine inhibited the intracellular proliferation of L. pneumophila in elicited macrophages, and this suppression was reversed by the additions of Fe-transferrin or ferric nitrilotriacetate. Fe-transferrin and ferric nitrilotriacetate did not further increase the intracellular proliferation of L. pneumophila in thioglycolate-elicited macrophages. However, ferric citrate and ferric nitrilotriacetate stimulated in a dose-dependent manner the growth of L. pneumophila in resident macrophages. Furthermore, equimolar concentrations of desferrioxamine reversed the stimulatory effect of iron in these resident cells. These data provide evidence supporting the hypothesis that differences in susceptibility to L. pneumophila growth between permissive elicited macrophages and nonpermissive resident macrophages from the A/J mouse strain are due to intracellular availability of iron.
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PMID:Macrophage permissiveness for Legionella pneumophila growth modulated by iron. 830 Feb 14


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