scholarly journals Aerosol infection of animals with strains ofLegionella pneumophilaof different virulence: comparison with intraperitoneal and intranasal routes of infection

1983 ◽  
Vol 90 (1) ◽  
pp. 81-89 ◽  
Author(s):  
R. B. Fitzgeorge ◽  
A. Baskerville ◽  
M. Broster ◽  
P. Hambleton ◽  
P. J. Dennis
Keyword(s):  
Legionella Pneumophila ◽  
Small Particle ◽  
Guinea Pigs ◽  
Rhesus Monkeys ◽  
Type Strain ◽  
Wide Range ◽  
Strain Nctc ◽  
Legionnaires Disease ◽  
Aerosol Infection ◽  
Intranasal Instillation

SUMMARYInfection of guinea-pigs by intranasal (i.n.) instillation of 109viable organisms of two newly isolated strains ofLegionella pneumophila(74/81, serogroup 1; 166/81, serogroup 3) did not induce disease, but 104organisms administered as a small particle aerosol (< 5 μm diameter) produced a fatal widespread bronchopneumonia within 3 days. Milder illness and less extensive bronchopneumonia were also produced in rhesus monkeys and marmosets by one of these two strains (74/81). Mice were resistant to induction of disease by aerosols of both these two strains, though organisms did persist in the lungs for at least 4 days. Both of theseL. pneumophilastrains were pathogenic for guinea-pigs by aerosol infection over a wide range of doses but the serogroup 1 type strain (NCTC 11192) was not. There was no mortality after infection of guinea-pigs by intranasal instillation of any of these strains but all proved to be fatal after intraperitoneal (i.p.) injection of large doses. Guinea-pigs, rhesus monkeys and marmosets exposed to aerosol infection withL. pneumophilaprovide relevant models for studying the pathogenesis of Legionnaires' disease.

scholarly journals A comparison of virulence of two strains ofLegionella pneumophilabased on experimental aerosol infection of guinea-pigs

1985 ◽  
Vol 95 (1) ◽  
pp. 29-38 ◽  
Author(s):  
R. I. Jepras ◽  
R. B. Fitzgeorge ◽  
A. Baskerville
Keyword(s):  
Experimental Evidence ◽  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
The Other ◽  
Avirulent Strain ◽  
Lung Macrophage ◽  
Other Hand ◽  
Strain Nctc ◽  
Aerosol Infection ◽  
Extracellular Location

SUMMARYTwo strains ofLegionella pneumophila(LP) serogroup I, of differing virulence, were examined in terms of numbers of viable organisms in tissues, pyrexia and mortality following aerosol infection. The Corby strain was the more virulent, with Pyrexia and deaths of guinea-pigs 3 to 6 days after infection. This strain multiplied very rapidly in the lungs to reach a peak of 5 × 1011viable organisms/lung. Organisms were present in the blood, liver, spleen and kidney. The Philadelphia-1 strain (NCTC 11192) was unable to replicate in the lung and was cleared between 14 and 21 days after infection. Pyrexia was not observed. No guinea-pigs died and viable LP was not found in any organ other than the lung.Lung lavages on aerosol infected animals were performed and the virulent Corby strain was found to be mainly intracellular. The avirulent Philadelphia-1 strain was found predominantly in the extracellular location. There were approximately 10 times the number of viable virulent LP in the lung macrophage fraction than in the lung PMNL fraction. In comparison, there were approximately equal numbers of the viable avirulent strain in the macrophages and the PMNL. Experimental evidence suggests that the macrophage preferentially supports the growth of the virulent Corby strain compared with the PMNL. The avirulent strain on the other hand appears to be destroyed by both the macrophages and the PMNL.

scholarly journals Peptidyl-Prolyl-cis/trans-Isomerases Mip and PpiB ofLegionella pneumophilaContribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
J. Rasch ◽  
C. M. Ünal ◽  
A. Klages ◽  
Ü. Karsli ◽  
N. Heinsohn ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Acanthamoeba Castellanii ◽  
Temperature Tolerance ◽  
Lung Damage ◽  
Atypical Pneumonia ◽  
Content Type ◽  
Wide Range ◽  
Legionnaires Disease ◽  
Environmental Fitness ◽  
Sliding Motility

ABSTRACTThe gammaproteobacteriumLegionella pneumophilais the causative agent of Legionnaires’ disease, an atypical pneumonia that manifests itself with severe lung damage.L. pneumophila, a common inhabitant of freshwater environments, replicates in free-living amoebae and persists in biofilms in natural and man-made water systems. Its environmental versatility is reflected in its ability to survive and grow within a broad temperature range as well as its capability to colonize and infect a wide range of hosts, including protozoa and humans. Peptidyl-prolyl-cis/trans-isomerases (PPIases) are multifunctional proteins that are mainly involved in protein folding and secretion in bacteria. InL. pneumophilathe surface-associated PPIase Mip was shown to facilitate the establishment of the intracellular infection cycle in its early stages. The cytoplasmic PpiB was shown to promote cold tolerance. Here, we set out to analyze the interrelationship of these two relevant PPIases in the context of environmental fitness and infection. We demonstrate that the PPIases Mip and PpiB are important for surfactant-dependent sliding motility and adaptation to suboptimal temperatures, features that contribute to the environmental fitness ofL. pneumophila. Furthermore, they contribute to infection of the natural hostAcanthamoeba castellaniias well as human macrophages and human explanted lung tissue. These effects were additive in the case of sliding motility or synergistic in the case of temperature tolerance and infection, as assessed by the behavior of the double mutant. Accordingly, we propose that Mip and PpiB are virulence modulators ofL. pneumophilawith compensatory action and pleiotropic effects.

scholarly journals Activities of Tigecycline (GAR-936) against Legionella pneumophila In Vitro and in Guinea Pigs with L. pneumophila Pneumonia

2003 ◽  
Vol 47 (2) ◽  
pp. 533-540 ◽  
Author(s):  
Paul H. Edelstein ◽  
William J. Weiss ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
Time Curve ◽  
Once Daily ◽  
Susceptibility Data ◽  
Days Of Therapy ◽  
Dosing Regimens ◽  
Legionnaires Disease

ABSTRACT The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp. strains was 4 μg/ml versus 0.125 and 0.25 μg/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 μg/ml) against the F889 strain of L. pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 μg/ml) was more active than (F889) or as active as (F2111) tigecycline (1 μg/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L. pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 μg/ml (1.2 and 1.5 μg/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 μg · h/ml, respectively. Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 × 106 CFU/g (range, 2.5 × 104 to 3.2 × 106 CFU/g) versus <1 × 102 CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear L. pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log10 4.2 to log10 5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular L. pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.

scholarly journals Legionnaires’ Disease Mortality in Guinea Pigs Involves the p45 Mobile Genomic Element

2019 ◽  
Vol 220 (10) ◽  
pp. 1700-1710
Author(s):  
Lanette M Christensen ◽  
Preeti Sule ◽  
Suat L G Cirillo ◽  
Madison Strain ◽  
Quinci Plumlee ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
Mobile Element ◽  
Interferon Γ ◽  
Secretion Systems ◽  
Proinflammatory Response ◽  
Disease Mortality ◽  
Genomic Element ◽  
Fatal Form ◽  
Legionnaires Disease

AbstractBackgroundLegionella can cause Legionnaires’ disease, a potentially fatal form of pneumonia that occurs as sporadic epidemics. Not all strains display the same propensity to cause disease in humans. Because Legionella pneumophila serogroup 1 is responsible for >85% of infections, the majority of studies have examined this serogroup, but there are 3 commonly used laboratory strains: L pneumophila serogroup 1 Philadelphia (Phil-1)-derived strains JR32 and Lp01 and 130b-derived strain AA100.MethodsWe evaluated the ability of Phil-1, JR32, Lp01, and AA100 to cause disease in guinea pigs.ResultsWe found that, although Phil-1, JR32, and AA100 cause an acute pneumonia and death by 4 days postinfection (100%), strain Lp01 does not cause mortality (0%). We also noted that Lp01 lacks a mobile element, designated p45, whose presence correlates with virulence. Transfer of p45 into Lp01 results in recovery of the ability of this strain to cause mortality, leads to more pronounced disease, and correlates with increased interferon-γ levels in the lungs and spleens before death.ConclusionsThese observations suggest a mechanism of Legionnaires’ disease pathogenesis due to the presence of type IVA secretion systems that cause higher mortality due to overinduction of a proinflammatory response in the host.

scholarly journals Invasion of Eukaryotic Cells byLegionella Pneumophila: A Common Strategy for all Hosts?

1997 ◽  
Vol 8 (3) ◽  
pp. 139-146 ◽  
Author(s):  
Paul S Hoffman
Keyword(s):  
Legionella Pneumophila ◽  
Human Infection ◽  
Host Cells ◽  
Eukaryotic Cells ◽  
Mature Form ◽  
Cellular Processes ◽  
Wide Range ◽  
Common Strategy ◽  
Legionnaires Disease ◽  
Host Parasite

Legionella pneumophilais an environmental micro-organism capable of producing an acute lobar pneumonia, commonly referred to as Legionnaires’ disease, in susceptible humans. Legionellae are ubiquitous in aquatic environments, where they survive in biofilms or intracellularly in various protozoans. Susceptible humans become infected by breathing aerosols laden with the bacteria. The target cell for human infection is the alveolar macrophage, in which the bacteria abrogate phagolysosomal fusion. The remarkable ability ofL pneumophilato infect a wide range of eukaryotic cells suggests a common strategy that exploits very fundamental cellular processes. The bacteria enter host cells via coiling phagocytosis and quickly subvert organelle trafficking events, leading to formation of a replicative phagosome in which the bacteria multiply. Vegetative growth continues for 8 to 10 h, after which the bacteria develop into a short, highly motile form called the ‘mature form’. The mature form exhibits a thickening of the cell wall, stains red with the Gimenez stain, and is between 10 and 100 times more infectious than agar-grown bacteria. Following host cell lysis, the released bacteria infect other host cells, in which the mature form differentiates into a Gimenez-negative vegetative form, and the cycle begins anew. Virulence ofL pneumophilais considered to be multifactorial, and there is growing evidence for both stage specific and sequential gene expression. Thus,L pneumophilamay be a good model system for dissecting events associated with the host-parasite interactions.

scholarly journals Detection of Legionella pneumonophila antigen in urine by enzyme-linked immunospecific assay

1979 ◽  
Vol 9 (5) ◽  
pp. 575-578
Author(s):  
B P Berdal ◽  
C E Farshy ◽  
J C Feeley
Keyword(s):  
Legionella Pneumophila ◽  
Guinea Pigs ◽  
Soluble Antigen ◽  
Sandwich Technique ◽  
American Legion ◽  
Pneumonia Patient ◽  
Legionnaires Disease ◽  
Urine Specimens

An enzyme-linked immunospecific assay "sandwich" technique was developed for detecting soluble antigen from the Legionnaires disease bacterium (Legionella pneumophila). With this technique, antigen was detected in urine specimens from guinea pigs inoculated intraperitoneally with heat-killed Legionnaires disease bacteria and in urine specimens from three of four patients who attended the American Legion Convention in Philadelphia in 1976. Urine from a fifth pneumonia patient who attended the Eucharistic Congress (but who was a dubious seroconverter) was negative. Presumably, the test could also be used for detecting antigen in sputum or respiratory aspirates, but this has not been tried to date.

scholarly journals In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia

2001 ◽  
Vol 45 (8) ◽  
pp. 2204-2209 ◽  
Author(s):  
Paul H. Edelstein ◽  
Takashi Shinzato ◽  
Edward Doyle ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Half Life ◽  
Guinea Pigs ◽  
Clinical Effectiveness ◽  
Drug Dose ◽  
Time Curve ◽  
Once Daily ◽  
Legionnaires Disease

ABSTRACT The activity of gemifloxacin against intracellularLegionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia was studied. Gemifloxacin, azithromycin, and levofloxacin (1 μg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 to 3 log10 units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy studies of gemifloxacin, azithromycin, and levofloxacin were performed in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route to infected guinea pigs, mean peak levels in plasma were 1.3 μg/ml at 0.5 h and 1.2 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area under the concentration-time curve from 0 to 24 h (AUC0–24) was 2.1 μg · h/ml. For the same drug dose, mean levels in lungs were 3.4 μg/g at both 0.5 and 1 h, with a half-life of 1.5 h and an AUC0–24 of 6.0 μg · h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once daily) for 2 days survived for 9 days after antimicrobial therapy, as did 13 of 14 guinea pigs treated with the same dose of gemifloxacin given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose given i.p. once daily for 2 days) survived, as did 11 of 12 animals treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is effective against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease, even with an abbreviated course of therapy. These data support studies of the clinical effectiveness of gemifloxacin for the treatment of Legionnaires' disease.

Histopathology of experimental Legionnaires' disease in guinea pigs, rhesus monkeys and marmosets

1983 ◽  
Vol 139 (3) ◽  
pp. 349-362 ◽  
Author(s):  
A. Baskerville ◽  
R. B. Fitzgeorge ◽  
M. Broster ◽  
P. Hambleton
Keyword(s):  
Guinea Pigs ◽  
Rhesus Monkeys ◽  
Legionnaires Disease

scholarly journals In Vitro Activity of ABT-773 againstLegionella pneumophila, Its Pharmacokinetics in Guinea Pigs, and Its Use to Treat Guinea Pigs with L. pneumophila Pneumonia

2001 ◽  
Vol 45 (10) ◽  
pp. 2685-2690 ◽  
Author(s):  
Paul H. Edelstein ◽  
F. Higa ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Half Life ◽  
Guinea Pigs ◽  
Clinical Effectiveness ◽  
Drug Dose ◽  
Drug Induced ◽  
Time Curve ◽  
Legionnaires Disease

ABSTRACT The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia. The ABT-773 MIC at which 50% of isolates are inhibited (MIC50) for 20 different Legionella sp. strains was 0.016 μg/ml, whereas the MIC50s of clarithromycin and erythromycin were 0.032 and 0.125 μg/ml, respectively. ABT-773 (1 μg/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages. In contrast, erythromycin and clarithromycin had easily reversible static activity only. Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophilapneumonia. When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 μg/ml at 0.5 h and 0.30 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC0–24) was 0.65 μg · h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 μg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC0–24 of 37.0 μg · h/ml. Ten of 15 L. pneumophila-infected guinea pigs treated with ABT-773 (15 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days post-antimicrobial therapy, as did 14 of 15 guinea pigs treated with erythromycin (30 mg/kg given intraperitoneally twice daily) for 5 days. All of the ABT-773-treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia. None of 12 animals treated with saline survived. ABT-773 is as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease. These data support studies of the clinical effectiveness of ABT-773 for the treatment of Legionnaires' disease.

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