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

Mice are highly resistant to Legionella pneumophila infection. To study the natural resistance, we used A/J and C57BL/6 mice which have macrophages permissive and non-permissive for the intracellular growth of L. pneumophila, respectively. The LD50 for A/J and C57BL/6 were 2.7 x 10(7) and 7.2 x 10(7) CFU, respectively, indicating that the difference in macrophage ability to regulate the bacterial growth had some effect on susceptibility to L. pneumophila. There was no difference between both strains in elimination of the bacteria from the blood stream within 5 h after infection. When mice were challenged intravenously with a sublethal dose (4 x 10(6) CFU), the bacterial burden in the liver at day 1 was significantly higher in A/J than in C57BL/6. The bacteria, thereafter, were eliminated rapidly from the liver at a similar rate in both strains. Elimination of the bacteria from the spleen and lungs was also delayed in A/J as compared to C57BL/6. Naive spleen cells of both strains in vitro could produce a large amount of interferon-gamma (IFN-gamma) one day after they were stimulated with formalin-killed L. pneumophila. When anti-murine IFN-gamma monoclonal antibody was administered, the bacterial burden in liver, spleen and lungs significantly increased in A/J, and also in C57BL/6 to some extent. We suggest that the innate macrophages' ability to regulate the intracellular bacterial growth and the endogenous IFN-gamma produced in a very early phase play a critical role in murine natural resistance against L. pneumophila infection.
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PMID:Investigation of the role of macrophages and endogenous interferon-gamma in natural resistance of mice against Legionella pneumophila infection. 159 5

Legionella pneumophila (Lp) grow in cultures in human, guinea pig, and mouse macrophages from A/J strain mice. Because exudate macrophages from this strain of mice have been reported deficient in responsiveness to lymphokines, we thought it of interest to document the extent of responsiveness to interferon-gamma in the context of growth restriction of Lp. Peritoneal exudate macrophages were obtained from A/J mice and cultured in either the presence or absence of recombinant interferon-gamma. These cultures were then infected with Lp and the extent of bacterial growth estimated 48 hr later by means of a colony-forming unit (CFU) assay and electron microscopy. Interferon-gamma treatment significantly restricted the number of CFUs in the culture at concentrations as low as 20 U/ml, but did not affect the uptake of bacteria by macrophages. Furthermore, treatment with interferon induced morphological changes consistent with activated macrophages. The involvement of oxygen-dependent mechanisms in phagocyte killing and growth restriction was examined by the use of inhibitors such as superoxide dismutase (SOD) and catalase. Neither one of these inhibitors of toxic oxygen metabolites affected the interferon-gamma-induced suppression of Lp growth. These results suggest that although thioglycolate-induced exudate macrophages from A/J mice support the growth of Lp, these cells readily respond to the activating influence of interferon-gamma. Furthermore, lymphokine treatment does not inhibit Lp uptake by macrophages and apparently restricts the growth of bacteria by mechanisms independent of the activity of toxic oxygen metabolites.
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PMID:Interferon-gamma induced resistance to Legionella pneumophila in susceptible A/J mouse macrophages. 189 14

We have previously reported that Legionella pneumophila antigens can induce interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) in vitro and in vivo in mice. Furthermore, treatment of murine polymorphonuclear leukocyte (PMN) cultures with these cytokines resulted in augmented killing of the bacteria in vitro. The purpose of the present study was to determine if these findings could be extended to human responses. Here we report that Legionella antigens induced IFN-gamma and TNF in nonimmune human leukocytes cultures, and that these cytokines were able to stimulate the bactericidal activity of isolated PMN against L. pneumophila in vitro. Furthermore, optimal production of IFN-gamma was found in cultures which were enriched for large granular lymphocytes (LGL). The phenotype of IFN-producing cells was determined to be CD11+, CD16+, CD2+, and negative for CD4, CD8, CD14, and Leu 7. Additionally, Legionella-infected monocytes were found to produce TNF in a dose-dependent response to the number of infecting bacteria, and the addition of recombinant IFN-gamma to infected monocytes resulted in augmented production of TNF in a synergistic manner. Finally, treatment of PMN with recombinant IFN-gamma and recombinant TNF augmented their bactericidal activity against Legionella in a dose-dependent response. Thus, cytokines which can be induced by L. pneumophila antigens are able to stimulate PMN function in vitro, suggesting that resistance to infection results from a complex interaction of cytokines and cell responses.
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PMID:Induction of interferon-gamma and tumor necrosis factor by Legionella pneumophila: augmentation of human neutrophil bactericidal activity. 249 51

We have examined the interaction between interferon-gamma (IFN-gamma)-activated human monocytes and Legionella pneumophila, the agent of Legionnaires' disease. Human monocytes activated with human recombinant IFN-gamma inhibit the intracellular multiplication of L. pneumophila. The degree of inhibition is proportional to the concentration of IFN-gamma, and maximal inhibition consistently occurs with greater than or equal to 2 micrograms/ml. Monoclonal anti-IFN-gamma antibody completely neutralizes the capacity of IFN-gamma to activate monocytes. Monocytes infected 24 hr after explantation maximally inhibit L. pneumophila multiplication if treated with IFN-gamma before infection or up to 2 hr after infection; treatment 6 hr or more after infection results in submaximal inhibition. Monocytes infected 48 hr after explantation inhibit L. pneumophila multiplication maximally if treated with IFN-gamma up to 12 hr before infection, but submaximally if treated at the time of infection. Once activated, monocytes inhibit L. pneumophila multiplication in the absence of IFN-gamma in the culture. Strikingly, monocytes maximally inhibit L. pneumophila multiplication after treatment with IFN-gamma for as briefly as 1 hr before infection. In the absence of anti-L. pneumophila antibody, neither IFN-gamma-activated monocytes nor nonactivated monocytes kill L. pneumophila. In the presence of specific antibody and complement, IFN-gamma-activated monocytes kill a proportion (0.5 log) of an inoculum but not more than nonactivated monocytes. L. pneumophila forms a specialized phagosome in IFN-gamma-activated monocytes that does not differ ultrastructurally from the L. pneumophila phagosome in nonactivated monocytes. These results demonstrate that IFN-gamma can activate human monocytes to exert a potent antimicrobial effect against a highly virulent intracellular bacterial pathogen. These findings extend previous observations on interactions between activated mononuclear phagocytes and L. pneumophila, and additionally support the hypothesis that cell-mediated immunity plays a major role in host defense against L. pneumophila.
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PMID:Interferon-gamma-activated human monocytes inhibit the intracellular multiplication of Legionella pneumophila. 309 80

We examined the ability of two recombinant human cytokines, granulocyte-macrophage colony-stimulating factor (rHu-GM-CSF) and interferon-gamma (rHu-IFN-gamma) to activate antibacterial mechanisms in human pulmonary macrophages (PM) and peripheral blood monocytes (PBM). Growth of Legionella pneumophila (LP) was assessed in PM or PBM which had been exposed to either rHu-IFN-gamma (500-1000 u/ml) or rHu-GM-CSF (1 to 10,000 u/ml). In both PM and PBM exposed to 500 u/ml rHu-IFN-gamma, growth of LP was reduced compared to cells exposed to media alone. By comparison, exposure of these cell types to rHu-GM-CSF had no detectable effect on bacterial replication. In order to investigate potential mechanisms accounting for this observation, the effect of these cytokines on the hydrogen peroxide (H2O2)-releasing capacity of cells was studied. Exposure of PM and PBM to rHu-IFN-gamma (500 to 1000 u/ml) resulted in increased production of H2O2 triggered by phorbol myristate acetate; when subjected to the same experimental conditions, rHu-GM-CSF-exposed cells exhibited no increase in H2O2 production. To further clarify the role of rHu-IFN-gamma-induced augmentation of oxidative metabolism on cellular inhibition of bacterial growth, an amount of catalase capable of completely neutralizing extracellular H2O2 was added to cells before and during infection. This did not abrogate the antibacterial activity of rHu-IFN-gamma. These studies demonstrate that rHu-IFN-gamma but not rHu-GM-CSF is capable of augmenting the capacity of PM and PBM to restrict LP growth. These data suggest that the antibacterial activity of rHu-IFN-gamma in this system may involve oxidative as well as nonoxidative mechanisms.
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PMID:Cytokine activation of antibacterial activity in human pulmonary macrophages: comparison of recombinant interferon-gamma and granulocyte-macrophage colony-stimulating factor. 314 84

The agent 1,25-dihydroxyvitamin D3 (D3) induces the differentiation of HL-60 human leukemia cells into functional monocyte-like cells that can support the intracellular multiplication of Legionella pneumophila. 22-Oxacalcitriol (OCT), a synthetic analogue of D3, exhibits greater differentiation-inducing activity than D3 in WEHI-3 mouse leukemia cells and has been suggested to be clinically more useful because of its lower hypercalcemic activity. The abilities of OCT and D3 to induce the functional differentiation of human leukemia HL-60 cells have now been investigated. OCT induced the differentiation of HL-60 cells into monocyte-like cells to a similar extent as D3. Thus, both OCT and D3 increased (1) the surface expression of CD11b, CD11c, CD14, and CD35; (2) nonspecific esterase staining; and (3) phagocytic activity toward fluorescent beads. HL-60 cells differentiated in response to OCT also supported the intracellular multiplication of L. pneumophila. Activation of both OCT- and D3-treated HL-60 cells with human recombinant interferon-gamma (IFN-gamma) for 24 h before infection markedly inhibited L. pneumophila multiplication. IFN-gamma activation enhanced superoxide anion generation by D3-treated HL-60 cells but not by OCT-treated HL-60 cells, suggesting that the inhibition of L. pneumophila multiplication in IFN-gamma-activated cells is independent of superoxide generation. Finally, D3, but not OCT, markedly stimulated the formation of osteoclast-like multinucleated cells from mouse bone marrow cells, consistent with the lower hypercalcemic activity of OCT.
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PMID:Intracellular multiplication of Legionella pneumophila in HL-60 cells functionally differentiated in response to 22-oxacalcitriol. 772 17

The role of host immune responses in the pathogenesis of Legionnaires' disease is incompletely understood, due in part to the current lack of an animal model that is both susceptible to replicative Legionella pneumophila-induced lung infection and for which species-specific immunological reagents are available. We have developed a model of replicative L. pneumophila lung infection in intratracheally inoculated A/J mice. L. pneumophila was obtained in the exponential growth phase and inoculated into the trachea of 6- to 8-week-old female A/J mice. Microbiological and histopathological evidence of infection was demonstrated in mice inoculated with 10(6) colony-forming units. Development of an acute pneumonia that resembled human Legionnaires' disease coincided with exponential growth of the bacteria in the lung 24 to 48 hours after intratracheal inoculation of L. pneumophila. This was associated with increased plasma levels of interferon-gamma at 24 hours after inoculation. After 48 hours, the bacteria were gradually eliminated from the lung over the next 5 days, corresponding with resolution of the inflammatory response in the lung, thereby mimicking the outcome frequently seen in the immunocompetent human host. Treatment of animals with anti-interferon-gamma antibody enhanced bacterial replication and disease progression, indicating an important role of host immune response in resolution of the infection. Because of the availability of murine-specific reagents, this model of replicative L. pneumophila lung infection in A/J mice after intrapulmonary inoculation of L. pneumophila potentially provides an important tool for future studies investigating the role of host immune responses in the pathogenesis of Legionnaires' disease in the immunocompetent host.
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PMID:Replicative Legionella pneumophila lung infection in intratracheally inoculated A/J mice. A murine model of human Legionnaires' disease. 799 56

To study the effects of recombinant interferon-gamma (IFN-gamma) on pulmonary defenses in vivo, we measured Ia antigen expression by alveolar macrophages and whole-lung clearance of inhaled Legionella pneumophila in normal and corticosteroid-treated rats. We found that Ia antigen was expressed by 7, 29, 50, and 65% of alveolar macrophages harvested from normal rats 24 h after intratracheal administration of 0, 10(3), 10(4), or 10(5) U of IFN-gamma, respectively, and by 76% of alveolar macrophages harvested from corticosteroid-treated rats given 10(5) U of IFN-gamma. Corticosteroid-treated rats exhibited a marked impairment in the clearance of inhaled L. pneumophila, associated with diminished release of IFN-gamma by antigen-stimulated splenocytes and blunted up-regulation of Ia antigen by alveolar-exudate macrophages. Daily intratracheal injections of IFN-gamma starting 1 day before or 1 day after infection had little effect on bacterial clearance in normal rats but markedly reduced the intrapulmonary replication of L. pneumophila and the number of bronchoalveolar neutrophils in corticosteroid-treated animals. Intraperitoneally administered IFN-gamma had no effect on Ia expression by alveolar macrophages or on bacterial clearance. IFN-gamma may be useful in the treatment of intracellular infections when targeted to the site of infection in immunosuppressed hosts.
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PMID:Intratracheal interferon-gamma augments pulmonary defenses in experimental legionellosis. 811 97

L-arginine-dependent reactive nitrogen intermediates have been identified as macrophage cytotoxic effector molecules against intracellular pathogens. To determine its role, ex vivo production of NO by peritoneal macrophages of C3H/HeN mice and Dunkin-Hartley guinea pigs infected intraperitoneally with a virulent and isogenic avirulent Legionella pneumophila serogroup 1 strain was compared with bacterial clearance from the lungs. While the virulent strain was cleared from mice lungs, the guinea pigs died within 96 h. In vivo infection with both strains resulted in the production of NO by mouse peritoneal macrophages ex vivo. In contrast, guinea pig macrophages did not produce detectable NO. In addition, infection by the avirulent strain led to the production of significantly more NO by mouse macrophages than the virulent parent strain, irrespective of stimulation with lipopolysaccharide (LP) and/or interferon-gamma (ifn-gamma). These results suggest that resistance to Leg. pneumophila infection may depend on the production of NO by host macrophages.
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PMID:Differential nitric oxide (NO) production by macrophages from mice and guinea pigs infected with virulent and avirulent Legionella pneumophila serogroup 1. 860 33

Nitric oxide (NO) is an intercellular messenger molecule produced by a variety of cells, including macrophages. However, the role of NO in infection, especially its immunological role, is poorly understood. In the present study, the role of NO in Legionella pneumophila-infected macrophages was examined. Whereas infection of mouse macrophages in vitro with L. pneumophila did not induce detectable NO, when the macrophages were primed with interferon-gamma (IFN-gamma), the treated macrophages markedly inhibited bacterial replication and produced a large amount of NO. Treatment with NO inhibitors, such as NG-monomethyl-L-arginine (L-MMA) or aminoguanidine, as well as culture in arginine-free medium, significantly inhibited NO production; however, the anti-L. pneumophila activity induced by IFN-gamma was not diminished. Examination of cytokine levels in L. pneumophila-infected macrophages primed with IFN-gamma revealed a moderate increase of interleukin-6 (IL-6) production; however, inhibition of NO by L-MMA markedly increased IL-6 production. Reconstitution of NO in the L. pneumophila-infected macrophages primed with IFN-gamma and treated with L-MMA to inhibit endogenous NO production following addition of sodium nitroprusside reduced IL-6 production to normal levels. The levels of IL-6 mRNA in L-MMA-treated macrophages were the same as in nontreated macrophages, as demonstrated by quantitative RT-PCR. Thus, these results indicate that NO may regulate IL-6 production independently of its role in antimicrobial function in L. pneumophila-infected macrophages and their immunoregulation on IL-6 production may be due to a post-transcriptional mechanism.
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PMID:Immunoregulatory role of nitric oxide in Legionella pneumophila-infected macrophages. 880 92


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