Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023241 (Legionella)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

We examined leukemic cells, HL-60, an acute promyelocytic leukemia cell line, after differentiation induced by 1,25-dihydroxyvitamin D3 (D3) and retinoic acid (A) for infection of Legionella pneumophila, the etiologic agent of Legionnaires' disease. We investigated the effect of interferon gamma (IFN-gamma) on the differentiated cells and on the intracellular growth of the bacteria. An examination of morphological and antigenic changes in the cells was also included in the study. After 4-day incubation with 10(-6)M D3 or A, the HL-60 cells differentiated into monocyte-like (D3-HL-60) or mature granulocyte-like (A-HL-60) cells, respectively. They were then infected with L. pneumophila. Intracellular multiplication of the bacteria was evident in D3-HL-60 cells but not in HL-60 or A-HL-60 cells. D3-HL-60 cells required a 24-h infection time for the intracellular growth of L. pneumophila. D3-HL-60 cells activated with human recombinant IFN-gamma for 1-24 h (gamma-IFN-D3-HL-60 cells) before infection markedly inhibited L. pneumophila multiplication, the effect of IFN-gamma being dose dependent. Surface marker analysis was carried out in HL-60, D3-HL-60, and gamma-IFN-D3-HL-60 cells. On D3-HL-60 cells, CD11b, CD11c, CD14, and CD35 antigen increased, whereas CD71 and HLA-DR antigen decreased. This finding suggested that HL-60 cells differentiated into monocyte-like cells; the acquisition of the complement receptors, CD11b(CR3) and CD35(CR1), seemed to be important for phagocytosis and for the subsequent intracellular multiplication of L. pneumophila. The gamma-IFN-D3-HL-60 cells showed an increase of CD16, CD36, CD71, and HLA-DR antigen, suggesting that they were in an activated state. Our study indicated, first, that D3 can induce human leukemic cells to differentiate into functional monocyte-macrophage-like cells that can support the intracellular multiplication of L. pneumophila and, second, that these differentiated leukemic cells can be activated by IFN-gamma to markedly inhibit bacterial growth.
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PMID:Intracellular multiplication of Legionella pneumophila in HL-60 cells differentiated by 1,25-dihydroxyvitamin D3 and the effect of interferon gamma. 833 78

The ability of Legionella species to multiply within human mononuclear phagocytes is usually regarded as being associated with their pathogenicity. Activation of host cells results in inhibition of intracellular Legionella multiplication. The most effective substance to induce macrophage activation, both in vivo and in vitro, is interferon-gamma. In addition, some evidence exists that macrophage-derived cytokines may contribute to the host defense against L. pneumophila, but the production of pro- and antiinflammatory cytokines by monocytes after infection with different Legionella species has not been reported with regard to their ability to multiply within the host cells. We therefore examined the production of TNF-alpha, IL-1, IL-6, IL-8, IL-10 and TGF-beta by Mono Mac 6 cells after infection with Legionella species of different human prevalence that differ in their ability to replicate within this macrophage-like cell line. After infection, Mono Mac 6 cells showed a cytokine response with time kinetics characteristic for the cytokine. Maximum cytokine levels produced differed with Legionella species, but were not related to intracellular multiplication rates. Moreover, LPS-tolerant Mono Mac 6 cells, which failed to produce cytokines, showed intracellular increase or decrease of bacterial numbers identical to that of untreated Mono Mac 6 cells. By FACS analysis, an up-regulation of CD14 (LPS receptor) and CD54 (ICAM-1) could be demonstrated. We conclude that, in the Mono Mac 6 cell line, induction of macrophage-derived cytokines after infection with members of the genus Legionella mimics an inflammatory reaction without association with intracellular multiplication rate.
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PMID:Induction of cytokines and expression of surface receptors in Mono Mac 6 cells after infection with different Legionella species. 953 66

Legionella pneumophila, a gram-negative bacterium causing Legionnaires' disease and Pontiac fever, was shown to be highly reactive in in vitro gelation of Limulus lysate but not able to induce fever and the local Shwartzman reaction in rabbits and mice. We analyzed the capacity of purified L. pneumophila lipopolysaccharide (LPS-Lp) to induce activation of the human monocytic cell line Mono Mac 6, as revealed by secretion of proinflammatory cytokines and desensitization to subsequent LPS stimulation. We showed that despite normal reactivity of LPS-Lp in the Limulus amoebocyte lysate assay, induction of cytokine secretion in Mono Mac 6 cells and desensitization to an endotoxin challenge required LPS-Lp concentrations 1,000 times higher than for LPS of Salmonella enterica serovar Minnesota. Therefore, we examined the interaction of LPS-Lp with the LPS receptor CD14. We demonstrated that LPS-Lp did not bind to membrane-bound CD14 expressed on transfected CHO cells, nor did it react with soluble CD14. Our results suggest that the low endotoxic potential of LPS-Lp is due to a failure of interaction with the LPS receptor CD14.
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PMID:Low endotoxic potential of Legionella pneumophila lipopolysaccharide due to failure of interaction with the monocyte lipopolysaccharide receptor CD14. 971 61

Lipopolysaccharide (LPS) derived from enterobacteria elicit in several cell types cellular responses that are restricted in the use of Toll-like receptor 4 (TLR4) as the principal signal-transducing molecule. A tendency to consider enterobacterial LPS as a prototypic LPS led some authors to present this mechanism as a paradigm accounting for all LPSs in all cell types. However, the structural diversity of LPS does not allow such a general statement. By using LPSs from bacteria that do not belong to the Enterobacteriaceae, we show that in bone marrow cells (BMCs) the LPS of Rhizobium species Sin-1 and of three strains of Legionella pneumophila require TLR2 rather than TLR4 to elicit the expression of CD14. In addition, exposure of BMCs from TLR4-deficient (C3H/HeJ) mice to the lipid A fragment of the Bordetella pertussis LPS inhibits their activation by the Legionella lipid A. The data show selective action of different LPSs via different TLRs, and suggest that TLR2 can interact with many lipid A structures, leading to either agonistic or specific antagonistic effects.
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PMID:Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow granulocytes via Toll-like receptor 2. 1248 15

Legionella pneumophila, the causative agent of Legionnaires' disease, is able to survive and multiply efficiently in a variety of mammalian cells. By using in vitro assays, the uptake of L. pneumophila into monocytes has shown to be mediated, at least in part, through attachment of complement-coated bacteria to complement receptors, but complement-independent phagocytosis could also be demonstrated. Since complement levels in the human lung are normally low, the role of complement-dependent phagocytosis in the pathogenesis of Legionnaires' disease is doubtful. However, the contribution of other potential phagocytosis-related host cell surface molecules to the phagocytosis of L. pneumophila has never been investigated. We therefore analyzed the role of complement receptors 1 (CD35) and 3 (CD11b/18), the lipopolysaccharide (LPS) receptor (CD14), the beta(1)-integrin chain of the fibronectin receptor (CD29), the intercellular adhesion molecule 1 (ICAM-1, CD54) and the transferrin receptor (CD71) in the complement-independent uptake of L. pneumophila. To exclude any influence of culture conditions onto phagocytosis rates, we compared a fresh clinical isolate with an agar-adapted isolate of L. pneumophila. In addition, we used three different host cell types (MM6, HeLa and Jurkat cells) expressing different rates of complement receptors. We could show that both strains of L. pneumophila were phagocytized by the three host cell lines to the same extent, but intracellular multiplication was only found in MM6 and, although to a much lesser degree, in Jurkat cells. Preincubation of MM6 cells with monoclonal antibodies directed against the above cited phagocytosis-related receptors did not result in inhibition of L. pneumophila uptake. We therefore conclude that typical phagocytosis-related cell surface receptors are not involved in the complement-independent phagocytosis of L. pneumophila.
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PMID:Investigation of mechanisms involved in phagocytosis of Legionella pneumophila by human cells. 1262 Jun 17

In this study, we analyzed the activation of bone-marrow derived dendritic cells (BMDCs) from mice lacking the cd14-gene with purified Legionella pneumophila lipopolysaccharide and with viable or formalin-killed L. pneumophila. We found that low concentrations of LPS and doses of L. pneumophila that are relevant to infection are dependent on CD14 to activate BMDCs. Higher concentrations of LPS are able to overcome the lack of CD14 indicating that other receptors areinvolved. We, therefore, included studies using BMDCs from mice lacking functional TLR2 and/or TLR4 molecules. We found that purified L. pneumophila LPS as well as L. pneumophila either viable or formalin-killed are able to activate BMDCs from TLR4-deficient C3H/HeJ mice but fail to activate BMDCs from TLR2-knockout mice. Our data show that not only purified LPS from L. pneumophila but also the microorganism itself stimulate BMDCs via TLR2 and that this stimulation is dependent on CD14 in this mouse model.
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PMID:Legionella pneumophila mediated activation of dendritic cells involves CD14 and TLR2. 1594 35

Legionella pneumophila is an opportunistic pathogen that in the environment colonizes biofilms and replicates within amoebae. The bacteria employ the intracellular multiplication/defective organelle trafficking (Icm/Dot) type IV secretion system to grow intracellularly in a specific vacuole. Using Acanthamoeba castellanii as a host cell, we have previously identified lcsC (Legionella cytotoxic suppressor), a paralogue of the lipid A disaccharide synthase lpxB, as a cytotoxic factor of L. pneumophila. A bioinformatic analysis of the genome revealed that L. pneumophila is unique in harbouring two paralogues of lpxB and two and three paralogues of the lipid A biosynthesis acyltransferases lpxA and lpxD, respectively. LcsC (lpxB1) forms a transcriptional unit with gnnA, encoding a putative UDP-GlcNAc oxidase in the biosynthetic pathway leading to 3-aminoglucosamine analogues of lipid A. LpxB2 clusters with lpxD2, lpxA2 and lpxL paralogues, encoding secondary acyltransferases. LcsC/lpxB1 and lpxB2 were found to partially complement the growth defect of an Escherichia coli lpxB conditional mutant strain, indicating that both corresponding enzymes possess lipid A disaccharide synthase activity. The two L. pneumophila lpxB paralogues are not functionally equivalent, since expression of lcsC/lpxB1 but not lpxB2 in an L. pneumophila icmG mutant is cytotoxic for A. castellanii, and LPS purified from the two strains triggers CD14-dependent tumour necrosis factor (TNF)alpha production by macrophages with a different potency. The lpxB and lpxA paralogues are expressed under various growth conditions, including broth, biofilms and in A. castellanii. While the flagellar gene flaA is mainly expressed in late stationary phase, the lpxB and lpxA paralogues are preferentially expressed in the exponential and early stationary phases. Upon exposure to hypotonic stress and nutrient deprivation, lpxA1, and to a lesser extent lcsC/lpxB1, is upregulated. The differential regulation of lpxB or lpxA paralogues in response to changing environmental conditions might allow L. pneumophila to adapt its lipid A structure.
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PMID:Expression of Legionella pneumophila paralogous lipid A biosynthesis genes under different growth conditions. 1797 91