Enhanced Macrophage Resistance to<i>Pseudomonas</i>Exotoxin A Is Correlated with Decreased Expression of the Low-Density Lipoprotein Receptor-Related Protein

Laithwaite, James E.; Benn, Sally J.; Yamate, Jyoji; FitzGerald, David J.; LaMarre, Jonathan

doi:10.1128/iai.67.11.5827-5833.1999

Cited by 21 publications

(6 citation statements)

References 47 publications

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“…Pseudomonas Exo‐A has been previously characterized as using CD91 as its unique cellular endocytic receptor (32,33). Fibroblasts deficient in CD91 neither endocytose Exo‐A nor are they susceptible to Exo‐A‐mediated cell death (33); macrophage susceptibility to Exo‐A correlates with cellular CD91 expression, and toxicity is inhibited by the presence of CD91 agonists (41). If CD91 is the unique, or even predominant, cellular receptor for CRT, then we would hypothesize that cellular interactions with CRT would parallel those of Exo‐A.…”

Section: Resultsmentioning

confidence: 99%

Differential CD91 Dependence for Calreticulin and Pseudomonas Exotoxin‐A Endocytosis

Walters

Berwin

2005

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Calreticulin (CRT) interaction with cell-surface receptors is integral to its function in escorting associated peptides into the antigen-presenting cell (APC) antigen presentation pathway. Additionally, extracellular CRT is proposed to be required for lung APC interaction with collectins. In both cases, CD91 has been proposed to act as the APC cell-surface receptor requisite for mediating these processes. However, the evidence for a CRT interaction with CD91 is indirect, predicated on partial competition of cellular binding by gp96, of which CD91 has been proposed as the unique endocytic receptor, and by the CD91 ligand a 2 -macroglobulin. Here, we directly investigate the function of CD91 in binding and trafficking CRT. We find that the ability of CRT to interact with APC does not correlate with cellular CD91 expression or function. Additionally, in the first genetic test of CD91 function regarding CRT, CD91 expression neither conferred CRT association nor did CD91-deficient (CD91 -/-) and CD91-expressing cells differ in their ability to traffic CRT. Finally, cellular CRT trafficking did not parallel that of Pseudomonas exotoxin-A, an obligate CD91 ligand, by the criteria of CD91 dependence, cell-type specificity and endocytic itinerary. These data identify that CRT trafficking is not, as previously hypothesized, CD91 dependent and indicate usage of alternative cellular trafficking pathways.

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Section: Resultsmentioning

confidence: 99%

Differential CD91 Dependence for Calreticulin and Pseudomonas Exotoxin‐A Endocytosis

Walters

Berwin

2005

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“…These toxins are important agents of human disease and are potential agents of bioterrorism (Balint, 1974;Boulton, 2003;Bradberry et al, 2003;Clarke, 2002;Dittmann et al, 2000;Franz & Zajtchuk, 2000;Lyczak et al, 2000;Madsen, 2001;O'Brien et al, 1992;Olsnes, 2004;Pickering et al, 1994;Tarr, 1995). Consequently, there is considerable interest in understanding how these toxins interact with host cells, with the ultimate goal of developing inhibitors of their action (Doring & Muller, 1989;Laithwaite et al, 1999;Ohmi et al, 1998;Sekino et al, 2004;Valdivieso-Garcia et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

A quantitative and highly sensitive luciferase-based assay for bacterial toxins that inhibit protein synthesis

Zhao

Haslam

2005

Journal of Medical Microbiology

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Inhibition of protein synthesis is a common mechanism by which bacterial and plant toxins injure human cells. Examples of toxins that inhibit protein synthesis include shiga toxins of Escherichia coli, diphtheria toxin, Pseudomonas exotoxin A and the plant toxin ricin. In order to facilitate studies on toxin pathogenesis and to enable screening for inhibitors of toxin action, a quantitative and highly sensitive assay for the action of these toxins on mammalian cells was developed. The cDNA encoding destabilized luciferase was cloned into an adenoviral expression plasmid and a high-titre viral stock was prepared. Following transduction of Vero cells, luciferase expression was found to be linear with respect to viral multiplicity of infection. Luciferase expression by as few as 10 cells was readily detected. Treatment of transduced cells with either cycloheximide or shiga toxin resulted in a decrease in luciferase activity, with a half-life ranging from 1 to 2 h. Inhibition of luciferase expression was evident at toxin concentrations as low as 1 pg ml À1 . The assay was adapted for use in 24-, 96-and 384-well plates, enabling rapid processing of large numbers of samples. Using this approach, susceptibility of Vero, Hep2, Chang, A549, COS-1 and HeLa cells to three different toxins was determined. These results demonstrate that the luciferase-based assay is applicable to the study of numerous cell types, is quantitative, highly sensitive and reproducible. These features will facilitate studies on pathophysiology of toxin-mediated diseases and allow high-throughput screening for inhibitors of cytotoxicity.

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“…Previous studies indicated the absence or reduce of LRP in different cell line, including LRP -/- embryonic fibroblasts, hepatoma and macrophage, were sufficient to protect cells from PEA intoxication [ 4 , 5 , 6 , 7 ]. These findings suggested that PEA might use LRP to gain entry into toxin-sensitive cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicated that the low-density lipoprotein receptor-related protein (LRP) functions as the receptor that PEA utilizes to gain access to mammalian cells [ 4 ]. In addition, the decreased expression of LRP may enhance macrophage and hepatocyte cell-line resistance to PEA induced cytotoxicity [ 5 , 6 ]. Laithwaite and collaborators reported that increased PEA sensitivity in BNL 1ME A7R.1 transformed hepatocytes was associated with increased functional cell surface LRP expression [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Differences in Genetic Background Contribute to Pseudomonas Exotoxin A-Induced Hepatotoxicity in Rats

Chiu

Wang

Huang

et al. 2017

Toxins

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Pseudomonas aeruginosa exotoxin A (PEA) causes severe hepatotoxicity in experimental animals and is useful in investigations of immune-mediated liver injury. However, strain differences in the sensitivity to PEA-induced hepatotoxicity in rats remains be elucidated. In this study, we determined the severity of PEA-induced hepatotoxicity in six genetically different rat strains. Male LE (Long Evans), Wistar, F344, WKY, BN/SsN and LEW rats were administered a single intravenous injection of PEA (20 μg/kg). Significantly elevated serum ALT and AST levels, massive necrosis and hemorrhage, and numerous TUNEL-positive hepatocytes were observed in BN/SsN rats. In contrast, low levels of ALT and AST as well as mild changes in liver histopathology were observed in Wistar and F344 rats. Moderate levels of hepatic injuries were observed in LE, WKY, and LEW rats. Pro-inflammatory cytokines including TNF-α, IL-2 and IL-6 serum levels were markedly increased in BN/SsN rats compared to Wistar and F344 rats. However, the hepatic levels of low density lipoprotein receptor-related protein (LRP), which functions as the PEA receptor, were not significantly different in each strain. Taken together, we suggest that BN/SsN is the most sensitive rat strain, whereas Wistar and F344 were the most resistant rat strains to PEA-induced liver damage. The different genetic background of rat strains plays an important role in the susceptibility to PEA-induced epatotoxicity that may depend on immune-regulation but not LRP receptor levels.

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Enhanced Macrophage Resistance toPseudomonasExotoxin A Is Correlated with Decreased Expression of the Low-Density Lipoprotein Receptor-Related Protein

Cited by 21 publications

References 47 publications

Differential CD91 Dependence for Calreticulin and Pseudomonas Exotoxin‐A Endocytosis

Differential CD91 Dependence for Calreticulin and Pseudomonas Exotoxin‐A Endocytosis

A quantitative and highly sensitive luciferase-based assay for bacterial toxins that inhibit protein synthesis

Differences in Genetic Background Contribute to Pseudomonas Exotoxin A-Induced Hepatotoxicity in Rats

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