The Lethal Events in Experimental Pseudomonas aeruginosa Infection of Mice

Bartell, Pasquale F.; Orr, Thomas E.; Garcia, Magaly

doi:10.1093/infdis/118.2.165

Cited by 29 publications

(11 citation statements)

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“…The activity in vitro of the polymyxins and aminoglycosides on P. aeruginosa is antagonized, to a variable degree, by Ca2+ and other factors in serum (9, 11-15, 30, 31, 40 The data available appear to exclude preformed toxins as a lethal factor in experimental murine infections (4,8,20). Toxins must become significant only after the infection is established.…”

Section: Discussionmentioning

confidence: 99%

Dissociation Between Results of In Vitro and In Vivo Antibiotic Susceptibility Tests for Some Strains of Pseudomonas aeruginosa

Davis

1974

Antimicrob Agents Chemother

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The relative efficacy in vivo of the polymyxin and aminoglycoside antibiotics in experimental Pseudomonas infection has apparently never been established. This study was designed to determine such efficacy in experimental infection of mice. Eleven strains of Pseudomonas aeruginosa were selected for the study, representing six of the seven recognized immunotypes. All strains were susceptible to colistin, gentamicin, and tobramycin in vitro, and all were virulent for mice. None was lethal because of preformed toxins. Infections were established in mice by intraperitoneal (i.p.) injection of 100 ID50 of bacteria (infectious doses that would kill 50% of the mice).

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Section: Discussionmentioning

confidence: 99%

Dissociation Between Results of In Vitro and In Vivo Antibiotic Susceptibility Tests for Some Strains of Pseudomonas aeruginosa

Davis

1974

Antimicrob Agents Chemother

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“…Pseudomonas aeruginosa produces a variety of extracellular substances (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Although the role of each of these substances in the pathogenesis of pseudomonas infections in humans is poorly understood, the most likely virulence factor is the trypsin-sensitive, heat-labile protein exotoxin (PA toxin) originally described by Liu (3).…”

mentioning

confidence: 99%

“…Protein synthesis in cultured 3T3 mouse cells is inhibited by 2 hr incubation with as little as 0.02 jug/ml of PA toxin, whereas at this concentration RNA synthesis is not inhibited until [4][5] hr incubation (L. P. Elwell and B. H. Iglewski, unpublished observations). However, the sequence of events by which PA toxin inhibits protein synthesis has not been established and it is not known whether the inhibition is a primary or secondary effect of PA toxin action.…”

mentioning

confidence: 99%

NAD-dependent inhibition of protein synthesis by Pseudomonas aeruginosa toxin,.

Iglewski¹,

Kabat²

1975

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

565

262

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Pseudomonas aeruginosa toxin (PA toxin) inhibits protein synthesis in a reticulocyte cell-free system. The inhibition requires NAD and results in a block at an elongation step of polypeptide assembly. PA Pseudomonas aeruginosa produces a variety of extracellular substances (1-11). Although the role of each of these substances in the pathogenesis of pseudomonas infections in humans is poorly understood, the most likely virulence factor is the trypsin-sensitive, heat-labile protein exotoxin (PA toxin) originally described by Liu (3). PA toxin in very low concentrations produces hypotensive shock in dogs (6) and monkeys (12) and is lethal for mice (4). Furthermore, passive immunization with antibody produced against PA toxin prevents the lethal effects of infection with live cultures of Pseudomonas aeruginosa (13).Previous data suggest that PA toxin inhibits RNA and protein synthesis in cultured mammalian cells (14) and protein synthesis in the liver, kidney, and spleen of intoxicated mice (15). Protein synthesis in cultured 3T3 mouse cells is inhibited by 2 hr incubation with as little as 0.02 jug/ml of PA toxin, whereas at this concentration RNA synthesis is not inhibited until 4-5 hr incubation (L. P. Elwell and B. H. Iglewski, unpublished observations). However, the sequence of events by which PA toxin inhibits protein synthesis has not been established and it is not known whether the inhibition is a primary or secondary effect of PA toxin action.This report describes the NAD-dependent inhibitory effect of PA toxin on protein synthesis in a rabbit reticulocyte cellfree lysate and identifies an enzymatic activity of PA toxin which appears to be similar to the NAD-dependent ADPribosyl transferase activity which has been established for the A-fragment of diphtheria toxin (16-18). In both cases elongation factor 2 (EF-2) is covalently modified and thereby inactivated. However, the two toxins are dissimilar in cellular specificities, molecular and immunological properties, and in the diseases for which they are apparently responsible. METHODS AND MATERIALSToxin and Antisera. A nonproteolytic strain of Pseudomonas aeruginosa (PA-103) kindly provided by P. V. Liu (19) was used throughout this study. PA toxin purified by precipitations with zinc acetate and (NH4)2SO4 and chromatographed on columns of DEAE-cellulose and Sephadex G-200 (20) Abbreviations: PA toxin, Pseudomonas aeruginosa toxin; EF-2, elongation factor 2.

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“…This also suggested the presence of an extracellular toxin. A study by Bartell, Orr and Garcia (1968) showed similar results in mice treated with a specific virulent-phage preparation; this significantly reduced the numbers of infecting organisms late in the course of infection without increasing survival. These workers suggested that the lethal process had already been initiated and was independent of continued microbial growth in the host.…”

Section: --mentioning

confidence: 74%

Experimental studies of the pathogenesis of Pseudomonas aeruginosa infection: evidence for the in-vivo production of a lethal toxin (Plate V)

Stieritz

Holder

1978

Journal of Medical Microbiology

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PLATE V I N a previous report (Stieritz and Holder, 1975) we described an experimental burned-mouse model that was particularly suitable for investigating the pathogenesis of Pseudomonas aeruginosa infection ; early events in the establishment of the infection within the burned host were studied and growth of the organism in vivo was examined by quantitative bacteriological procedures. The results suggested that a lethal toxin was produced at the site of infection in the burned skin, and histological studies supported this hypothesis.Earlier investigators suggested that a lethal, diffusible toxin is produced by P. aeruginosa in the wounds of burned patients (Moncrief and Teplitz, 1964; Alexander, 1971). Furthermore, the degree of toxaemia was found to be related to the concentration of organisms in the burned tissues (Alexander, 1971).Our earlier studies suggested that the mouse model might be useful in the study of infection of burns, and this communication reports further experimental evidence that P. aeruginosa growing in burned tissues produces a lethal toxin. MATERIALS AND METHODS Animals andprocedures.All experiments were performed with female CF1 mice (Carworth Farms) weighing 22-24 g. Animals were housed in wire cages and given food and water ad libitum.The procedure used in producing burns has previously been described (Holder and Jogan, 1971). Anaesthetised mice were given a 10-s burn with an ethanol flame on the shaved back involving approximately 30 % of the total body surface. Immediately thereafter approximately 100 organisms in 0.5 ml of physiological saline (PS) were injected subcutaneously in the burned area. Burned but uninfected control animals received 0.5 ml of sterile PS instead of bacterial suspension. P. aeruginosa. Throughout these studies a single strain, originally isolated from the intestinal tract of a normal CF1 mouse (Stieritz and Holder, 1975), was used.Counts of P. aeruginosa in tissues and organs. Counts in the burned skin, livers and spleens of infected animals were determined, either immediately post rnortern or at the time stated, by the method of Saymen et al. (1972). Results are expressed as the loglo of the count per gram (wet weight) of tissue.

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The Lethal Events in Experimental Pseudomonas aeruginosa Infection of Mice

Cited by 29 publications

References 0 publications

Dissociation Between Results of In Vitro and In Vivo Antibiotic Susceptibility Tests for Some Strains of Pseudomonas aeruginosa

Dissociation Between Results of In Vitro and In Vivo Antibiotic Susceptibility Tests for Some Strains of Pseudomonas aeruginosa

NAD-dependent inhibition of protein synthesis by Pseudomonas aeruginosa toxin,.

Experimental studies of the pathogenesis of Pseudomonas aeruginosa infection: evidence for the in-vivo production of a lethal toxin (Plate V)

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