Legionella pneumophila pathogenesis and immunity.
TL;DR: New findings are described that demonstrate that various cytokines that define Th1 vs Th2 helper cell activity also are important in regulating resistance versus susceptibility to this ubiquitous microorganism.
About: This article is published in Seminars in Pediatric Infectious Diseases.The article was published on 2002-10-01. It has received 100 citations till now. The article focuses on the topics: Legionella pneumophila & Adoptive immunity.
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TL;DR: It is demonstrated that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11–dependent, cell-autonomous immunity in response to cytoplasmic LPS, and a role is suggested for Gbpchr3 proteins in the detection of cy toplasmo LPS and the activation of the noncanonical inflammasome.
Abstract: IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11-dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11-dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila. The rapid induction of pyroptosis in IFN-activated macrophages required a cluster of IFN-inducible Gbp proteins encoded on mouse chromosome 3 (Gbp(chr3)). Induction of pyroptosis in naive macrophages by infections with the cytosol-invading ΔsdhA L. pneumophila mutant was similarly dependent on Gbp(chr3), suggesting that these Gbp proteins play a role in the detection of bacteria accessing the cytosol. Cytoplasmic LPS derived from Salmonella ssp. or Escherichia coli has recently been shown to trigger caspase-11 activation and pyroptosis, but the cytoplasmic sensor for LPS and components of the caspase-11 inflammasome are not yet defined. We found that the induction of caspase-11-dependent pyroptosis by cytoplasmic L. pneumophila-derived LPS required Gbp(chr3) proteins. Similarly, pyroptosis induced by cytoplasmic LPS isolated from Salmonella was diminished in Gbp(chr3)-deficient macrophages. These data suggest a role for Gbp(chr3) proteins in the detection of cytoplasmic LPS and the activation of the noncanonical inflammasome.
286 citations
Cites background from "Legionella pneumophila pathogenesis..."
...Proc Natl Acad Sci USA 110(1):294–299....
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...Clearance of these pulmonary infections requires IFN-mediated immune responses (1)....
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...pneumophila can infect alveolar macrophages and cause pneumonia in humans and animal models (1)....
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TL;DR: Although the Dot/Icm secretion system of Legionella pneumophila elicits an early robust activation of caspase‐3 in human macrophages, it triggers a strong anti‐apoptotic signalling cascade mediated, at least in part by NF‐κB, which renders the cells refractory to external potent apoptotic stimuli.
Abstract: The Dot/Icm type IV secretion system of Legionella pneumophila triggers robust activation of caspase-3 during early and exponential stages of proliferation within human macrophages, but apoptosis is delayed till late stages of infection, which is novel. As caspase-3 is the executioner of the cell, we tested the hypothesis that L. pneumophila triggers anti-apoptotic signalling within the infected human macrophages to halt caspase-3 from dismantling the cells. Here we show that during early and exponential replication, L. pneumophila-infected human monocyte-derived macrophages (hMDMs) exhibit a remarkable resistance to induction of apoptosis, in a Dot/Icm-dependent manner. Microarray analyses and real-time PCR reveal that during exponential intracellular replication, L. pneumophila triggers upregulation of 12 anti-apoptotic genes that are linked to activation of the nuclear transcription factor kappa-B (NF-kappaB). Our data show that L. pneumophila induces a Dot/Icm-dependent sustained nuclear translocation of the p50 and p65 subunits of NF-kappaB during exponential intracellular replication. Bacterial entry is essential both for the anti-apoptotic phenotype of infected hMDMs and for nuclear translocation of the p65. Using p65-/- and IKKalpha-/- beta-/- double knockout mouse embryonic fibroblast cell lines, we show that nuclear translocation of NF-kappaB is required for the resistance of L. pneumophila-infected cells to apoptosis-inducing agents. In addition, the L. pneumophila-induced nuclear translocation of NF-kappaB requires the activity of IKKalpha and/or IKKbeta. We conclude that although the Dot/Icm secretion system of L. pneumophila elicits an early robust activation of caspase-3 in human macrophages, it triggers a strong anti-apoptotic signalling cascade mediated, at least in part by NF-kappaB, which renders the cells refractory to external potent apoptotic stimuli.
136 citations
Cites background from "Legionella pneumophila pathogenesis..."
...pneumophila in infected macrophages in vitro as well as in the lungs of experimental animals (Brieland et al., 1995; Friedman et al., 2002)....
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...Although antiapoptotic events are predicted to benefit the pathogen by maintaining viability of the replicative niche, proinflammation has been shown to limit and control the infection by L. pneumophila (Brieland et al., 1995; Friedman et al., 2002)....
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...…signalling, NF-kB is involved in expression of pro-inflammatory cytokines (Medzhitov, 2001; Barton and Medzhitov, 2003), which are triggered by L. pneumophila in infected macrophages in vitro as well as in the lungs of experimental animals (Brieland et al., 1995; Friedman et al., 2002)....
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...…Journal compilation © 2006 Blackwell Publishing Ltd, Cellular Microbiology, 9, 246–264 involved in the expression of pro-inflammatory cytokines (Medzhitov, 2001; Barton and Medzhitov, 2003), many of which are triggered by L. pneumophila, such as TNF-a (Brieland et al., 1995; Friedman et al., 2002)....
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TL;DR: In this paper, the authors reported the application of isotopologue profiling for analyzing the metabolism of Legionella pneumophila (Lp) and reported that the identification of protein-derived amino acids and poly-3-hydroxybutyrate was determined by mass spectrometry and/or NMR spectroscopy.
107 citations
TL;DR: In this paper, a real-time PCR method was developed for the detection and simultaneous identification of Legionella pneumophila Sg1 in clinical and environmental isolates, and the selected primers with 454 Legionella and 38 non-Legionella strains demonstrated 100% specificity.
Abstract: Legionella pneumophila, a bacterium that replicates within aquatic amoebae and persists in the environment as a free-living microbe, is the causative agent of Legionnaires' disease. Among the many Legionella species described, L. pneumophila is associated with 90% of human disease, and within the 15 serogroups (Sg), L. pneumophila Sg1 causes more than 84% of Legionnaires' disease worldwide. Thus, rapid and specific identification of L. pneumophila Sg1 is of the utmost importance for evaluation of the contamination of collective water systems and the risk posed. Previously we had shown that about 20 kb of the 33-kb locus carrying the genes coding for the proteins involved in lipopolysaccharide biosynthesis (LPS gene cluster) by L. pneumophila was highly specific for Sg1 strains and that three genes (lpp0831, wzm, and wzt) may serve as genetic markers. Here we report the sequencing and comparative analyses of this specific region of the LPS gene cluster in L. pneumophila Sg6, -10, -12, -13, and -14. Indeed, the wzm and wzt genes were present only in the Sg1 LPS gene cluster, which showed a very specific gene content with respect to the other five serogroups investigated. Based on this observation, we designed primers and developed a classical and a real-time PCR method for the detection and simultaneous identification of L. pneumophila Sg1 in clinical and environmental isolates. Evaluation of the selected primers with 454 Legionella and 38 non-Legionella strains demonstrated 100% specificity. Sensitivity, specificity, and predictive values were further evaluated with 209 DNA extracts from water samples of hospital water supply systems and with 96 respiratory specimens. The results showed that the newly developed quantitative Sg1-specific PCR method is a highly specific and efficient tool for the surveillance and rapid detection of high-risk L. pneumophila Sg1 in water and clinical samples.
104 citations
TL;DR: These studies show that Nod1, Nod2, and Rip2 account for generation of innate immune responses in vivo, which are important for NE recruitment and bacterial clearance in a murine model of Legionnaires diseases.
98 citations
References
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TL;DR: An explosive, common-source outbreak of pneumonia caused by a previously unrecognized bacterium affected primarily persons attending an American Legion convention in Philadelphia in July, 1976, killing 29 people, and epidemiologic analysis suggested that exposure may have occurred in the lobby of the headquarters hotel or in the area immediately surrounding the hotel.
Abstract: An explosive, common-source outbreak of pneumonia caused by a previously unrecognized bacterium affected primarily persons attending an American Legion convention in Philadelphia in July, 1976. Twenty-nine of 182 cases were fatal. Spread of the bacterium appeared to be air borne. The source of the bacterium was not found, but epidemiologic analysis suggested that exposure may have occurred in the lobby of the headquarters hotel or in the area immediately surrounding the hotel. Person-to-person spread seemed not to have occurred. Many hotel employees appeared to be immune, suggesting that the agent may have been present in the vicinity, perhaps intermittently, for two or more years.
1,468 citations
TL;DR: It is concluded that Legionnaires' disease is caused by a gram-negative bacterium that may be responsible for widespread infection.
Abstract: To identify the etiologic agent of Legionnaire's disease, we examined patients' serum and tissue specimens in a search for toxins, bacteria, fungi, chlamydiae, rickettsiae and viruses. From the lungs of four of six patients we isolated a gram-negative, non-acid-fast bacillus in guinea pigs. The bacillus could be transferred to yolk sacs of embryonated eggs. Classification of this organism is incomplete. We used yolk-sac cultures of the bacillus as antigen to survey suspected serum specimens, employing antihuman-globulin fluorescent antibody. When compared to controls, specimens from 101 to 111 patients meeting clinical criteria of Legionnaires' disease showed diagnostic increases in antibody titers. Diagnostic increases were also found in 54 recent sporadic cases of severe pneumonia and, retrospectively, in stored serum from most patients in two other previously unsolved outbreaks of respiratory disease. We conclude that Legionnaires' disease is caused by a gram-negative bacterium that may be responsible for widespread infection.
1,173 citations
TL;DR: Following the discovery of Legionella pneumophila as the cause of an epidemic of pneumonia at an American Legion convention in Philadelphia, a group of related bacteria were recognized as additional human pathogens, which include the agents of Legionnaires' disease, Pittsburgh pneumonia, and several related infections.
189 citations
TL;DR: The historical background, epidemiology, microbiology, and clinical manifestations of these newly-discovered organisms are reviewed in comparative fashion.
170 citations
TL;DR: Evidence is provided supporting the hypothesis that differences in susceptibility to L. pneumophila growth between permissive elicited macrophage and nonpermissive resident macrophages from the A/J mouse strain are due to intracellular availability of iron.
Abstract: 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.
53 citations