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

Legionella pneumophila, the causative agent of legionellosis, is an intracellular parasite of human monocytic cells and neutrophils. The life cycle of Legionella within phagocytic cells is distinct from that of other bacterial pathogens. Adherence of L pneumophila to phagocytes is mediated by attachment of complement proteins to the Legionella cell surface, followed by binding to complement receptors of phagocytes. Opsonized Legionella also may enter phagocytes after engagement of the Fc receptors. Within the host cell, the parasites reside in a membrane-bound vacuole that does not fuse with lysosomes. Activation of mononuclear phagocytes by the cell-mediated immune system serves to limit intracellular bacterial growth. Polymorphonuclear leukocytes are better at killing L pneumophila than are macrophages. However, Legionella also can invade and parasitize granulocytes. Although significant progress has been made in understanding some aspects of the pathogenesis of legionellosis, we know very little about the mechanisms by which these facultative intracellular parasites avoid killing by host defense mechanisms. This is an important area for future research and should lead to a better understanding of host-parasite interactions.
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PMID:Legionella pneumophila: denizen of defenders. 188 68

We have studied the interaction between virulent Legionella pneumophila and human alveolar macrophages, the resident phagocytes at the site of infection in Legionnaires' disease. L. pneumophila multiplied 2.5-5 logs within 3 d, as measured by colony forming units, when incubated with freshly explanted alveolar macrophages in monolayer culture. At the peak of bacterial multiplication, the alveolar macrophage monolayers were destroyed. L. pneumophila multiplied more rapidly in 4-d-old than in freshly explanted alveolar macrophages. Inside alveolar macrophages, L. pneumophila were located within membrane-bound vacuoles whose cytoplasmic sides were studded with ribosomes. Alveolar macrophages that were incubated with concanavalin A (Con A) stimulated human mononuclear cell supernatants (cytokines), inhibited L. pneumophila multiplication, and the degree of inhibition was proportional to the concentration of Con A supernatant added. Anti-L. pneumophila antibody in conjunction with complement promoted phagocytosis of L. pneumophila by alveolar macrophages. By electron microscopy, most (75%) of the phagocytized L. pneumophila were intracellular. However, freshly explanted alveolar macrophages were able to kill only 0-10% of an innoculum of L. pneumophila even in the presence of antibody and complement. At the same time, alveolar macrophages also killed opsonized Escherichia coli poorly. Increasing the ratio of macrophages to bacteria, adhering the macrophages to microcarrier beads, or preincubating the macrophages for 24 or 48 h with Con A supernatants failed to augment alveolar macrophage killing of opsonized E. coli. Corticosteroids appear to increase patient susceptibility to Legionnaires' disease. However, pretreatment of alveolar macrophages and monocytes with hydrocortisone had no influence on intracellular multiplication of L. pneumophila or on the inhibition of that multiplication by activated alveolar macrophages or monocytes. Hydrocortisone did impair cytokine-induced aggregation of alveolar macrophages. These findings demonstrate that L. pneumophila multiplies in human alveolar macrophages and that they do so within a ribosome-lined phagosome; that freshly explanted alveolar macrophages kill few L. pneumophila even in the presence of antibody and complement; that activated alveolar macrophages inhibit L. pneumophila multiplication; and that steroids do not exert a direct suppressive effect on the anti-L. pneumophila activity of activated or nonactivated alveolar macrophages. Our findings indicate that alveolar macrophages may play a central role in both the pathogenesis of Legionnaires' disease and in host defense against it. This paper shows that human resident macrophage can be activated to a higher state of antimicrobial capacity and that the human alveolar macrophage can serve as an effector call in call-mediated immunity.
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PMID:Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. 647 Jan 40

We have previously reported that virulent egg yolk-grown Legionella pneumophila, Philadelphia 1 strain, multiplies intracellularly in human blood monocytes and only intracellularly under tissue culture conditions. In this paper, we have investigated the effect of erythromycin and rifampin on L. pneumophila-monocyte interaction in vitro; erythromycin and rifampin are currently the drugs of choice for the treatment of Legionnaires' disease. The intracellular multiplication of L. pneumophila is inhibited by erythromycin and rifampin, as measured by colony-forming units, whether the antibiotics are added just before or just after infection of monocytes with L. pneumophila, or 2 d after infection when L. pneumophila is in the logarithmic phase of growth in monocytes. Intracellular multiplication of L. pneumophila is inhibited by 1.25 microgram/ml but not less than or equal to 0.125 microgram/ml erythromycin and 0.01 microgram/ml but not less than or equal to 0.001 microgram/ml rifampin. These concentrations of antibiotics are comparable to those that inhibit extracellular multiplication of L. pneumophila under cell-free conditions in artificial medium; the minimal inhibitory concentration is 0.37 microgram/ml for erythromycin and 0.002 microgram/ml for rifampin. Multiplication of L. pneumophila in the logarithmic phase of growth in monocytes is inhibited within 1 h of the addition of antibiotics. Intracellular bacteria inhibited from multiplying by antibiotics are not killed. By electron microscopy, the bacteria appear intact within membrane-bound vacuoles, studded with ribosomelike structures. L. pneumophila multiplying extracellularly on artificial medium is killed readily by relatively low concentrations of erythromycin and rifampin; the minimal bactericidal concentration is 1 microgram/ml for erythromycin and 0.009 microgram/ml for rifampin. In contrast, L. pneumophila multiplying intracellularly is resistant to killing by these concentrations of erythromycin and rifampin or by concentrations equal to or greater than peak serum levels in humans. Extracellular L. pneumophila in stationary phase is also resistant to killing by erythromycin and rifampin. These findings, taken together with our previous work, indicate that, in vivo, L. pneumophila is resistant to killing by erythromycin and rifampin. Inhibition of L. pneumophila multiplication in monocytes by antibiotics is reversible; when the antibiotics are removed from infected monocyte cultures after 2 d, L. pneumophila resumes multiplication. This study indicates that patients with Legionnaires' disease under treatment with erythromycin and rifampin require host defenses to eliminate L. pneumophila, and that inadequate host defenses may result in relapse after cessation of therapy.
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PMID:Intracellular multiplication of Legionnaires' disease bacteria (Legionella pneumophila) in human monocytes is reversibly inhibited by erythromycin and rifampin. 684 56

We have studied the interaction between virulent egg yolk-grown Legionella pneumophila Philadelphia 1 and human blood monocytes in vitro. The leukocytes were cultured in antibiotic-free tissue culture medium supplemented with 15% autologous human serum.L. pneumophila multiplied several logs, as measured by colony-forming units, when incubated with monocytes or mononuclear cells; the mid-log phase doubling time was 2 h. The level to which L. pneumophila multiplied was proportional to the number of mononuclear cells in the culture. L. pneumophila multiplied only in the adherent fraction of the mononuclear cell population indicating that monocytes but not lymphocytes support growth of the bacteria. Peak growth of L. pneumophila was correlated with destruction of the monocyte monolayer. By fluorescence microscopy using fluorescein conjugated rabbit anti-L. pneumophila antiserum, the number of monocytes containing L. pneumophila increased in parallel with bacterial growth in the culture. At the peak of infection, monocytes were packed full with organisms. By electron microscopy, L. pneumophila in such monocytes were found in membrane-bound cytoplasmic vacuoles studded with structures resembling host cell ribosomes. Several lines of evidence indicate that L. pneumophila grows within monocytes. (a) In the absence of leukocytes, L. pneumophila did not grow in tissue culture medium with or without serum even if the medium was conditioned by monocytes. (b) L. pneumophila did not grow in sonicated mononuclear cells. Lysis of these cells at various times during logarithmic growth of L. pneumophila was followed by cessation of bacterial multiplication. Growth resumed when intact mononuclear cells were added back to the culture. (3) In parabiotic chambers separated by 0.1-mum Nuclepore filters, L. pneumophila multiplied only when placed on the same side of the filter as mononuclear cells. These findings indicate that L. pneumophila falls into a select category of bacterial pathogens that evade host defenses by parasitizing monocytes. It remains to be determined whether cell-mediated immunity plays a dominant role in host defense against L. pneumophila as it does against other intracellular pathogens.
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PMID:Legionnaires' disease bacterium (Legionella pneumophila) multiples intracellularly in human monocytes. 719 May 79

Numerous intracellular bacterial pathogens modulate the nature of the membrane-bound compartment in which they reside, although little is known about the molecular basis for this control. Legionella pneumophila is a bacterial pathogen able to grow within human alveolar macrophages and residing in a phagosome that does not fuse with lysosomes. This study demonstrates that the dotA product is required to regulate trafficking of the L. pneumophila phagosome. Phagosomes containing L. pneumophila dotA+ bacteria exhibited differential trafficking profiles when compared with isogenic dotA mutants. Phagosomes containing dotA mutants showed rapid accumulation of the lysosomal glycoprotein LAMP-1 as early as 5 min after uptake, whereas the majority of wild-type L. pneumophila phagosomes did not acquire LAMP-1. The association of LAMP-1 with phagosomes containing dotA mutant bacteria was concomitant with the appearance of the small GTP-binding protein Rab7 on the vacuolar membrane. These data demonstrate that phagosomes containing replication-competent L. pneumophila evade early endocytic fusion events. In contrast, the kinetics of LAMP-1 and Rab7 association indicate that the dotA mutants are routed along a well-characterized endocytic pathway leading to fusion with lysosomes. Genetic studies show that L. pneumophila requires DotA expression before macrophage uptake in order to establish an intracellular site for replication. However, the bacteria do not appear to require continuous expression of the DotA protein to maintain a replicative phagosome. These data indicate that DotA is one factor that plays a fundamental role in regulating initial phagosome trafficking decisions either upon or immediately after macrophage uptake.
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PMID:Legionella pneumophila DotA protein is required for early phagosome trafficking decisions that occur within minutes of bacterial uptake. 963 67

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

Conditions were established in which Legionella pneumophila, an intracellular bacterial pathogen, could replicate within the unicellular organism Dictyostelium discoideum. By several criteria, L. pneumophila grew by the same mechanism within D. discoideum as it does in amoebae and macrophages. Bacteria grew within membrane-bound vesicles associated with rough endoplasmic reticulum, and L. pneumophila dot/icm mutants, blocked for growth in macrophages and amoebae, also did not grow in D. discoideum. Internalized L. pneumophila avoided degradation by D. discoideum and showed evidence of reduced fusion with endocytic compartments. The ability of L. pneumophila to grow within D. discoideum depended on the growth state of the cells. D. discoideum grown as adherent monolayers was susceptible to L. pneumophila infection and to contact-dependent cytotoxicity during high-multiplicity infections, whereas D. discoideum grown in suspension was relatively resistant to cytotoxicity and did not support intracellular growth. Some known D. discoideum mutants were examined for their effect on growth of L. pneumophila. The coronin mutant and the myoA/B double myosin I mutant were more permissive than wild-type strains for intracellular growth. Growth of L. pneumophila in a G(beta) mutant was slightly reduced compared to the parent strain. This work demonstrates the usefulness of the L. pneumophila-D. discoideum system for genetic analysis of host-pathogen interactions.
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PMID:Intracellular growth of Legionella pneumophila in Dictyostelium discoideum, a system for genetic analysis of host-pathogen interactions. 1076 92

The gram-negative respiratory pathogen Legionella pneumophila infects and grows within mammalian macrophages and protozoan host cells. Upon uptake into macrophages, L. pneumophila establishes a replicative organelle that avoids fusion with endocytic vesicles. There are 24 dot/icm genes on the L. pneumophila chromosome required for biogenesis of this vacuole. Many of the Dot/Icm proteins are predicted to be components of a membrane-bound secretion apparatus similar to type IV conjugal transfer systems. We have been investigating the function of L. pneumophila dot/icm gene products that do not have obvious orthologs in other type IV transfer systems, since these determinants could govern processes unique to phagosome biogenesis. The icmX gene product falls into this category. To understand the role of the IcmX protein in pathogenesis, we have detailed interactions between an L. pneumophila icmX deletion mutant and murine bone marrow-derived macrophages. These data demonstrate that icmX is required for biogenesis of the L. pneumophila replicative organelle. Immunoblot analysis indicates that the icmX gene product is a polypeptide with an estimated molecular mass of 50 kDa. The IcmX protein was localized to the bacterial periplasm, and periplasmic translocation was mediated by an N-terminal sec-dependent leader peptide. A truncated IcmX product was secreted into culture supernatants by wild-type L. pneumophila growing extracellularly in liquid media; however, transport of the IcmX protein into eukaryotic host cells was not detected. Proteins similar in molecular weight to IcmX were identified in other Legionella species by immunoblot analysis using a monoclonal antibody specific for L. pneumophila IcmX protein. From these data, we conclude that the IcmX protein is an essential component of the dot/icm secretion apparatus, and that a conserved mechanism of host cell parasitism exists for members of the Legionellaceae family.
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PMID:Identification and subcellular localization of the Legionella pneumophila IcmX protein: a factor essential for establishment of a replicative organelle in eukaryotic host cells. 1085 11

Key to the pathogenesis of intracellular pathogens is their ability to manipulate host cell processes, permitting the establishment of an intracellular replicative niche. In turn, the host cell deploys defence mechanisms that limit intracellular infection. The bacterial pathogen Legionella pneumophila, the aetiological agent of Legionnaire's Disease, has evolved virulence mechanisms that allow it to replicate within protozoa, its natural host. Many of these tactics also enable L. pneumophila's survival and replication inside macrophages within a membrane-bound compartment known as the Legionella-containing vacuole. One of the virulence factors indispensable for L. pneumophila's intracellular survival is a type IV secretion system, which translocates a large repertoire of bacterial effectors into the host cell. These effectors modulate multiple host cell processes and in particular, redirect trafficking of the L. pneumophila phagosome and mediate its conversion into an ER-derived organelle competent for intracellular bacterial replication. In this review, we discuss how L. pneumophila manipulates host cells, as well as host cell processes that either facilitate or impede its intracellular survival.
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PMID:Host cell processes that influence the intracellular survival of Legionella pneumophila. 1836 81

The pathogenesis of Legionella pneumophila is derived from its growth within lung macrophages after aerosols are inhaled from contaminated water sources. Interest in this bacterium stems from its ability to manipulate host cell vesicular-trafficking pathways and establish a membrane-bound replication vacuole, making it a model for intravacuolar pathogens. Establishment of the replication compartment requires a specialized translocation system that transports a large cadre of protein substrates across the vacuolar membrane. These substrates regulate vesicle traffic and survival pathways in the host cell. This Review focuses on the strategies that L. pneumophila uses to establish intracellular growth and evaluates why this microorganism has accumulated an unprecedented number of translocated substrates that are targeted at host cells.
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PMID:The Legionella pneumophila replication vacuole: making a cosy niche inside host cells. 1901 59


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