Legionnaires' Disease

Fraser, David W.; Tsai, Theodore R.; Orenstein, Walter A.; Parkin, William E.; Beecham, H. James; Sharrar, Robert G.; Harris, Jonathan; Mallison, George F.; Martin, S. M.; McDade, Joseph E.; Shepard, Charles C.; Brachman, Philip S.

doi:10.1056/nejm197712012972201

Cited by 1,521 publications

(253 citation statements)

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“…It is believed that inhalation of aerosols containing either freeliving L. pneumophila or amoeba laden with the bacteria leads to colonization of the lungs. Phagocytosed L. pneumophila then grow within alveolar macrophages in a fashion similar to that observed with amoeba (2, 3), eventually causing a severe form of pneumonia known as Legionnaires' disease (4).…”

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confidence: 80%

IcmR-regulated Membrane Insertion and Efflux by the Legionella pneumophila IcmQ Protein

Duménil

Montminy

Tang

et al. 2004

Journal of Biological Chemistry

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Legionella pneumophila proliferates within alveolar macrophages as a central property of Legionnaires' disease. Intracellular growth involves formation of a replicative phagosome, which requires the bacterial Dot/Icm system, a multiprotein secretion apparatus that translocates proteins from the bacterium across the macrophage plasma membrane. Two components of this system, IcmR and IcmQ, are proposed to exhibit a chaperone/substrate relationship similar to that observed in other protein translocation systems. We report here that IcmQ inserts into lipid membranes and forms pores that allow the efflux of the dye calcein but not Dextran 3000. Both membrane insertion and pore formation were inhibited by IcmR. Trypsin digestion mapping demonstrated that IcmQ is subdivided into two functional domains. The N-terminal region of IcmQ was necessary and sufficient for insertion into lipid membranes and calcein efflux. The C-terminal domain was necessary for efficient association of the protein with lipid bilayers. IcmR was found to bind to the N-terminal portion of the protein thus providing a mechanism for its ability to inhibit IcmQ pore-forming activity. Localization of IcmQ on the surface of the L. pneumophila shortly after infection as well as its pore-forming capacities suggest a role for IcmQ in forming a channel that leads translocated effectors out of the bacterium.

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confidence: 80%

IcmR-regulated Membrane Insertion and Efflux by the Legionella pneumophila IcmQ Protein

Duménil

Montminy

Tang

et al. 2004

Journal of Biological Chemistry

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“…Since the first outbreak of Legionnaires' disease (LD) at the American Legion convention in 1976 [1], Legionella pneumophila has been a relatively common pathogen of community-acquired pneumonia (CAP). The reported incidence of LD in CAP ranges from 1.6% to 7.5% [2][3][4][5][6] and that in severe CAP is between 14% and 22.8%) [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor

Kaku

Yanagihara

Morinaga

et al. 2013

Journal of Infection and Chemotherapy

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A 65-year-old man was admitted to our hospital with a fever of 39.3°C, cough, sputum and pharyngeal discomfort that had persisted for three days. Rheumatoid arthritis had been treated with methotrexate and adalimumab for two years and pancreatic metastasis of gastric cancer had been treated with S-1 (tegafur, gimeracil, and oteracil potassium) for two months. Regardless of the underlying pathologies, his general condition was good and he had worked as an electrician until two days before admission. However, his appetite had suddenly decreased from the day before admission, and high fever and hypoxia were also evident upon admission. A chest X-ray and computed tomography scan revealed left pleural effusion and consolidation in both lungs. The pneumonia severity index score was 165 and risk class was V. Accordingly, we started to treat the pneumonia with a combination of levofloxacin and meropenem. Thereafter, we received positive urinary antigen test (UAT) findings for Legionella pneumophila. Despite the application of appropriate antibiotics, vasopressors and oxygenation, the hypotension and hypoxia progressed and the patient died eight hours after admission. Even after his death, blood cultures had been continued to consider the possibility of bacterial co-infection. Although no bacteria were detected from blood cultures, Gimenez staining 3 revealed pink bacteria in blood culture fluids. Subsequent blood fluid culture in selective medium revealed L. pneumophila serogroup 1.

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“…Because of their central role in regulation of the immune response to pathogens, TLRs are excellent candidate genes for genetic susceptibility studies (6). Legionella pneumophila, described in 1976 as the agent of Legionnaires' disease (LD), is a flagellated Gram-negative bacterium that causes from 1% to 30% of cases of community-acquired pneumonia (7)(8)(9)(10)(11). In vitro studies indicate that Legionella is recognized by several TLRs, including TLR2, TLR4, and TLR5 (12)(13)(14)(15).…”

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Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Hawn

Verbon

Janer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

154

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The immunogenetic factors that influence susceptibility to pneumonia are poorly understood. Recent studies suggest an association of toll-like receptor 4 (TLR4) polymorphisms with increased susceptibility to some infections. Here, we examined whether polymorphisms in TLR4 influence susceptibility to Legionnaires' disease (LD) by using a case-control study to compare the allele frequencies of two SNPs (A896G and C1196T). Cases (n ‫؍‬ 108) were obtained from a LD outbreak in The Netherlands in 1999. Controls were exposed at the same outbreak, did not develop pneumonia, and were either unmatched (n ‫؍‬ 421) or matched (n ‫؍‬ 89) to patients for age, sex, and geographic residence. Allele 896G was associated with LD susceptibility with a frequency of 6.5% in the combined control group (matched and unmatched) vs. Although previous studies suggest that these TLR4 SNPs are associated with an increased risk of infection, this study demonstrates an association with resistance. This protective association illustrates that an innate immune receptor can mediate either beneficial or deleterious inflammatory responses and that these outcomes vary with different pathogens.genetic markers ͉ immunity ͉ inflammation A lthough lower respiratory tract infections are the most common cause of death due to infectious disease in the United States, the influence of host immunogenetic factors on human susceptibility to pneumonia is poorly understood (1). Toll-like receptors (TLRs) constitute a family of transmembrane proteins that differentially recognize pathogen-associated molecular patterns through an extracellular domain and initiate inflammatory signaling pathways through an intracellular domain (2-5). Because of their central role in regulation of the immune response to pathogens, TLRs are excellent candidate genes for genetic susceptibility studies (6). Legionella pneumophila, described in 1976 as the agent of Legionnaires' disease (LD), is a flagellated Gram-negative bacterium that causes from 1% to 30% of cases of community-acquired pneumonia (7-11). In vitro studies indicate that Legionella is recognized by several TLRs, including TLR2, TLR4, and TLR5 (12-15). We recently demonstrated (13,16,17) that TLR5 recognizes bacterial flagellin and that a common dominant TLR5 stop codon variant is associated with susceptibility to LD. It is not known whether polymorphisms in other TLRs influence human susceptibility to LD. TLR4, the receptor for lipopolysaccharide (LPS), has two common polymorphisms (A896G and C1196T) that are associated with LPS hyporesponsiveness in heterozygous individuals in response to inhaled endotoxin (18). Although several small genetic studies suggest a possible association of these SNPs in heterozygous individuals with an increased risk of some bacterial infections, the influence of these SNPs on human infections remains poorly understood and controversial (19)(20)(21)(22)(23). Furthermore, inflammatory responses of heterozygous individuals are not uniformly impaired, and the result appears to depend on the mea...

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Legionnaires' Disease

Cited by 1,521 publications

References 4 publications

IcmR-regulated Membrane Insertion and Efflux by the Legionella pneumophila IcmQ Protein

IcmR-regulated Membrane Insertion and Efflux by the Legionella pneumophila IcmQ Protein

Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor

Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

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