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

To elucidate the role of the oxidative burst in macrophage resistance to Legionella infection, we examined a murine macrophage-like cell line, J774.1, for permissiveness to Legionella growth, using a mutant that has a selective defect in the oxidative burst after lipopolysaccharide (LPS) stimulation. Legionella pneumophila serogroup 1 was infected into J774.1 monolayers, and then the extent of bacterial growth was estimated by a CFU assay. Both the parental cell line, JA-4, and the LPS-resistant mutant, LPS1916, were permissive for Legionella growth but became nonpermissive after pretreatment with gamma interferon. However, pretreatment of LPS1916 cells with LPS failed to inhibit bacterial growth, although LPS-treated JA-4 cells exhibited inhibited multiplication of the bacteria. The bacterial growth inhibition in JA-4 and mutant LPS1916 cells was correlated with the extent of the oxidative burst in the cells, as judged by cytochrome c reduction but not nitrite production. Neither transferrin receptor expression nor the iron content in JA-4 and LPS1916 cells, with or without LPS treatment, was correlated with suppression of Legionella growth. These results suggest that the restriction of Legionella growth in J774.1 cells is due to a bactericidal effect of the oxidative burst rather than reduction of the iron supply to the intracellular bacteria and that the effectors are reactive oxygen intermediates and not reactive nitrogen intermediates.
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PMID:Difference in Legionella pneumophila growth permissiveness between J774.1 murine macrophage-like JA-4 cells and lipopolysaccharide (LPS)-resistant mutant cells, LPS1916, after stimulation with LPS. 796 Jan 21

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

Infection of macrophages with Legionella pneumophila induces formation of interleukin 1 beta (IL-1 beta), but the molecular basis of this is not understood. Binding of bacteria to macrophage surfaces is the first step in an infection process. Therefore, we examined whether this step was sufficient to increase the cellular level of mRNAs for IL-1 beta and other cytokines. To assess the effect of binding of L. pneumophila on the steady-state levels of cytokine mRNAs, cultures of thioglycolate-elicited macrophages from L. pneumophila-susceptible A/J mice were treated with cytochalasin D and infected with L. pneumophila and the total RNA was extracted for analysis by reverse transcription-PCR with primers for IL-1 alpha, IL-1 beta, IL-6, tumor necrosis factor alpha, granulocyte macrophage colony-stimulating factor, and beta interferon (IFN-beta). L. pneumophila treatment increased the cellular steady-state mRNA levels of all cytokines except IFN-beta. To determine the specificity of this effect, macrophage cultures were treated with cytochalasin D and either bacterial lipopolysaccharide, bovine serum albumin-sensitized latex, Salmonella typhimurium, or Escherichia coli. Lipopolysaccharide treatment increased all mRNAs, bovine serum albumin-sensitized latex had no significant effect, and treatment with S. typhimurium or E. coli increased all mRNAs except that of IFN-beta. These results suggested that the binding of gram-negative bacteria to the macrophage surface was sufficient to induce a unique pattern of cytokine mRNAs. Additional studies that examined the characteristics of the bacterial ligands involved indicated involvement of both heat-labile and heat-stable surface ligands.
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PMID:Binding of Legionella pneumophila to macrophages increases cellular cytokine mRNA. 806 12

Resistance to infection with Legionella pneumophila is primarily dependent upon cell-mediated immunity rather than humoral immunity. Recent evidence suggests that activation of cell-mediated immunity depends on Th1 cells and activation of humoral immunity depends on Th2 cells. In this report, delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid of marijuana and an immunomodulator, suppressed development of secondary immunity to L. pneumophila, which correlated with a reduction in Th1 activity. BALB/c mice, infected with a primary sublethal dose of L. pneumophila, developed resistance to a larger challenge infection 3 to 4 weeks later. However, intravenous injection of THC (4 mg/kg of body weight) 1 day prior to primary infection resulted in increased mortality after the challenge infection. The level of anti-L. pneumophila antibodies in serum increased in both THC-treated and control mice; however, in the THC group IgG1 antibodies which are stimulated by Th2 cells were elevated while Th1-regulated, IgG2a antibodies were depressed. Furthermore, cultured splenocytes from THC-treated mice had less L. pneumophila-specific lymphoproliferation, indicating a deficiency in cell-mediated immunity. Normal mouse splenocytes treated in vitro with THC and pokeweed mitogen showed suppressed production of gamma interferon, a cytokine associated with Th1 cells, but increased production of interleukin 4, a cytokine produced by Th2 cells. Splenocytes from THC-treated mice, stimulated in vitro with either pokeweed mitogen or anti-CD3 antibodies, also produced less gamma interferon, indicating less Th1 activity in these mice. These results suggest that THC decreases the development of anti-L. pneumophila immunity by causing a change in the balance of Th1 and Th2 activities.
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PMID:Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection. 806 21

We investigated the role of tumor necrosis factor alpha (TNF-alpha) in human peripheral monocytes infected with Legionella pneumophila in vitro. Exogenous TNF-alpha significantly inhibited the intracellular multiplication of the bacterium. This effect was concentration and time dependent and was abrogated by anti-TNF antibodies. TNF-alpha levels in the culture supernatants were low but were enhanced by the addition of gamma interferon. When monocytes were cultured and infected in the presence of pentoxyphilline, a potent inhibitor of TNF-alpha synthesis, the intracellular bacterial growth was enhanced. The effect of pentoxyphilline was concentration and time dependent and was due to the inhibition of TNF-alpha production, as shown by Northern (RNA) blot hybridization of total RNA. In addition, the pentoxyphilline partially abolished the inhibitory effect of gamma interferon on bacterial intracellular multiplication. These results suggest that gamma interferon inhibits, at least partially, the intracellular multiplication of L. pneumophila by enhancing TNF-alpha synthesis.
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PMID:Involvement of tumor necrosis factor alpha in intracellular multiplication of Legionella pneumophila in human monocytes. 822 72

Macrophages can be activated by lipopolysaccharides (LPS) from gram-negative bacteria to evince a number of biological activities, including increased resistance to intracellular infection by opportunistic bacteria. In the present study, intraperitoneal injection of LPS into A/J mice activated peritoneal macrophages so that they resisted subsequent in vitro infection with Legionella pneumophila. Coculture of these macrophages with those from nontreated A/J mice converted the entire population of cells from permissive to nonpermissive. This effect did not appear to be mediated by soluble factors released from the LPS-treated macrophages, since the levels of interleukins-1 and -6 and tumor necrosis factor alpha produced by the macrophages were not found to be markedly elevated at the time when the macrophages from the LPS-treated mice were most effective in converting normal macrophages to nonpermissiveness. Furthermore, macrophages from mice injected intraperitoneally with either interferon or tumor necrosis factor alpha did not evince nonpermissiveness and also did not have the ability to convert normal spleen cells to nonpermissiveness. Polymyxin B, a known inactivator of LPS activity, did not inhibit the macrophages from the LPS-treated mice from inducing this resistance. It seemed unlikely that free LPS released from the macrophages mediated this effect. The results of this study thus showed that macrophages activated by LPS in vivo can evince nonpermissiveness for Legionella growth in vitro and also can induce macrophages from normal, permissive mice to become nonpermissive for Legionella growth in vitro.
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PMID:Legionella pneumophila growth restriction in permissive macrophages cocultured with nonpermissive lipopolysaccharide-activated macrophages. 822 82

The effect of inhaled amoebae on the pathogenesis of Legionnaires' disease was investigated in vivo. A/J mice, which are susceptible to replicative Legionella pneumophila infections, were inoculated intratracheally with L. pneumophila (10(6) bacteria per mouse) or were coinoculated with L. pneumophila (10(6) bacteria per mouse) and Hartmannella vermiformis (10(6) amoebae per mouse). The effect of coinoculation with H. vermiformis on bacterial clearance, histopathology, cellular recruitment into the lung, and intrapulmonary levels of cytokines including gamma interferon and tumor necrosis factor alpha was subsequently assessed. Coinoculation with H. vermiformis significantly enhanced intrapulmonary growth of L. pneumophila in A/J mice. Histopathologic and flow cytometric analysis of lung tissue demonstrated that while A/J mice inoculated with L. pneumophila alone develop multifocal pneumonitis which resolves with minimal mortality, mice coinoculated with H. vermiformis develop diffuse pneumonitis which is associated with diminished intrapulmonary recruitment of lymphocytes and mononuclear phagocytic cells and significant mortality. Furthermore, coinoculation of mice with H. vermiformis resulted in a fourfold enhancement in intrapulmonary levels of gamma interferon and tumor necrosis factor alpha compared with mice infected with L. pneumophila alone. The effect of H. vermiformis on intrapulmonary growth of L. pneumophila in a resistant host (i.e., BALB/c mice) was subsequently evaluated. While BALB/c mice do not develop replicative L. pneumophila infections following inoculation with L. pneumophila alone, there was an eightfold increase in intrapulmonary L. pneumophila in BALB/c mice coinoculated with H. vermiformis. These studies, demonstrating that intrapulmonary amoebae potentiate replicative L. pneumophila lung infection in both a susceptible and a resistant host, have significant implications with regard to the potential role of protozoa in the pathogenesis of pulmonary diseases due to inhaled pathogens and in the design of strategies to prevent and/or control legionellosis.
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PMID:Coinoculation with Hartmannella vermiformis enhances replicative Legionella pneumophila lung infection in a murine model of Legionnaires' disease. 869 66

The differentiation of HL-60, a human leukemic cell line, into monocyte-like cells (D3-HL-60 cells) is induced by 1,25-dihydroxyvitamin D3 (D3). We examined the effects of interferon (IFN) treatment of D3-HL-60 cells on the expression of cell surface antigens, the phagocytic activity for fluorescent beads, production of oxygen radicals, and intracellular growth of Legionella pneumophila. Activation of D3-HL-60 cells with IFN-gamma, Beta, and alpha for 24 h significantly increased expression of CD16, CD36, CD71, and HLA-DR antigens. IFN-gamma markedly enhanced the phagocytic activity of beads in D3-HL-60 cells. There was no significant difference in phagocytic activity between cells exposed to IFN-alpha or beta and untreated D3-HL-60 cells. IFN-alpha, beta, and gamma enhanced production of oxygen radicals, including superoxide, by D3-HL-60 cells. Superoxide production was enhanced to the greatest degree by IFN-gamma, followed by IFN-beta and then IFN-gamma. Intracellular growth of L. pneumophila in D3-HL-60 cells was inhibited by interferons (IFN-gamma > beta > gamma). Similar results were obtained in human mononuclear cells. These data indicate that interferons can act as biologic response modifiers not only in human mononuclear cells but also in differentiated leukemic cells. Our results may have implications for the development of differentiation therapy for treatment of leukemia.
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PMID:Effects of interferon-alpha, beta, and gamma on the function of differentiated leukemic HL-60 cells induced by 1,25-dihydroxyvitamin D3. 872 74

Legionella pneumophila is an intracellular parasite of alveolar macrophages, and recovery from legionellosis is associated with activation of alveolar macrophages to resist intracellular bacterial replication. Gamma interferon (IFN-gamma) is known to activate alveolar macrophages to suppress L. pneumophila, but the role of macrophage-derived cytokines in modulating alveolar macrophage resistance is unknown. To test the hypothesis that macrophage-derived mediators contribute to the resistance of alveolar macrophages to L. pneumophila, we incubated adherent rat alveolar macrophages with Escherichia coli lipopolysaccharide (LPS), recombinant tumor necrosis factor alpha (TNF-alpha), recombinant IFN-gamma, neutralizing anti-TNF-alpha, and/or N(G)-monomethyl-L-arginine (L-NMMA) for 6 h before challenge with L. pneumophila. Monolayers were sonically disrupted and quantitatively cultured on successive days. We also measured bioactive TNF-alpha release by infected macrophages in the presence or absence of IFN-gamma. We found that pretreatment of alveolar macrophages with LPS or, to a lesser degree, TNF-alpha, significantly inhibited intracellular replication of L. pneumophila. Both LPS and TNF-alpha acted synergistically with IFN-gamma at less than the maximally activating concentration to suppress L. pneumophila growth. The independent and coactivating effects of LPS were blocked by anti-TNF-alpha. Killing of L. pneumophila by IFN-gamma at the maximally activating concentration was inhibited by anti-TNF-alpha. The synergistic effects of TNF-alpha. or LPS in combination with IFN-gamma were inhibited by L-NMMA. Infected alveolar macrophages secreted TNF-alpha in proportion to the bacterial inoculum, and secretion of TNF-alpha was potentiated by cocultivation with IFN-gamma. These data indicate that secretion of TNF-alpha is an important autocrine defense mechanism of alveolar macrophages, serving to potentiate the activating effects of IFN-gamma through costimulation of nitric oxide synthesis.
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PMID:Roles for tumor necrosis factor alpha and nitric oxide in resistance of rat alveolar macrophages to Legionella pneumophila. 875 59

To facilitate identification of the effector mechanism(s) responsible for gamma interferon (IFN-gamma)-mediated host resistance to Legionella pneumophila, a murine model of legionellosis in BALB/c mice with a targeted disruption in the IFN-gamma gene (gamma knockout [GKO] mice) was developed. Immunocompetent BALB/c mice and GKO mice were inoculated intratracheally with virulent L. pneumophila (10(6) bacteria per mouse), and bacterial clearance and the pulmonary inflammatory response were assessed. L. pneumophila did not replicate in, and was rapidly cleared from, the lungs of immunocompetent BALB/c mice, demonstrating that immunocompetent BALB/c mice are resistant to replicative L. pneumophila pulmonary infections. In contrast, similarly infected GKO mice developed persistent, replicative intrapulmonary L. pneumophila infections with extrapulmonary dissemination of the bacteria to the spleen. Histopathologic and flow cytometric analysis of L. pneumophila-infected lung tissue demonstrated that while immunocompetent BALB/c mice develop multifocal pneumonitis which resolves, similarly infected GKO mice develop diffuse pneumonitis with persistent neutrophil recruitment into the lung. Intratracheal administration of exogenous IFN-gamma to L. pneumophila-infected GKO mice facilitated intrapulmonary clearance of the bacteria, confirming the pivotal role of IFN-gamma in innate host defenses to L. pneumophila lung infection in this murine host. The potential role of endogenous reactive nitrogen intermediates, including nitric oxide (NO), in IFN-gamma-mediated resistance to L. pneumophila pulmonary infections in immunocompetent BALB/c mice was subsequently assessed. Macrophage inducible nitric oxide synthetase (an enzyme responsible for the production of NO) was induced in alveolar cells from L. pneumophila-infected immunocompetent BALB/c mice (with maximal expression at 48 h postinfection) but was not induced in similarly infected GKO mice. However, administration of the NO synthetase inhibitor N-monomethyl-L-arginine did not significantly inhibit clearance of L. pneumophila from the lung of immunocompetent BALB/c mice (compared with that in similarly infected mice not administered N-monomethyl-L-arginine). In contrast, we have previously demonstrated that IFN-gamma-induced host resistance to replicative L. pneumophila lung infections in a susceptible murine host (A/J mice) is mediated, in part, by endogenous NO. Taken together, these studies identify a differing role of endogenous NO in IFN-gamma-mediated resistance to L. pneumophila pulmonary infection in susceptible and resistant murine hosts.
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PMID:Effector mechanisms responsible for gamma interferon-mediated host resistance to Legionella pneumophila lung infection: the role of endogenous nitric oxide differs in susceptible and resistant murine hosts. 894 59


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