Structural data suggest that there is no high-valency binding of PE to its receptor (Wedekind et al., 2001). The production of this cellular toxin is affected by iron levels.P. The toxoid was prepared from exotoxin A taken from toxigenic strains of P. aeruginosa (PA 103). The initial step of glucose metabolism takes place in the periplasm and includes the oxidation of glucose to 2-ketogluconate, which enters the cytoplasm to be further metabolized. Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells. Curr. J. Mol. 50 mice were immunized with the toxoid, burned with hot metal and infected with 1 108 . doi: 10.1111/j.1742-4658.2010.07775.x, Farajnia, S., Peerayeh, S. N., Tanomand, A., Majidi, J., Goudarzi, G., Naghili, B., et al. Pharmacol. Initially, the PE-fragment binds to NAD+ and interacts via the so-called active-site loop L4 (aa 483490 of domain III) with eEF-2 (Yates and Merrill, 2004). Genet. Burns. Background Pseudomonas aeruginosa is the leading cause of nosocomial infections, especially in people with a compromised immune system. [5] found that immunization with a combination of alkaline protease and toxoid of exotoxin A decreased mortality. doi: 10.1046/j.1365-2958.1996.321396.x, Douzi, B., Filloux, A., and Voulhoux, R. (2012). After 24 h, 108 colony forming units (CFU) of toxigenic strains of P. aeruginosa (PA 103) were inoculated subcutaneously into the burned area. Refined crystallographic structure of Pseudomonas aeruginosa exotoxin A and its implications for the molecular mechanism of toxicity. N. Engl. 10.1093/nar/gks1039 The infections range from endophtalmitis, endocard itis, meningitis, and . doi: 10.1016/S1074-7613(00)00013-3. Rev. Pseudomonas aeruginosa (Pa) 1,2 is a significant cause of nosocomial infections in health care settings. NK assistant in immunological methods. The slide was subjected to electrophoresis using an acetate buffer (pH 7.6 at 40 mA for 30 min). (2004). Interestingly, the unfolding step in the EE for furin cleavage is also discussed to lead to a masquerade of the PE molecule as an unfolded/misfolded protein to be successfully transported to the cytosol (Pelham et al., 1992). doi: 10.1139/cjm-2014-0501, Gellatly, S. L., and Hancock, R. E. (2013). 1984 Sep;120(3):271-9. doi: 10.1002/jcp.1041200303. doi: 10.1042/BJ20031731, Zerial, M., and McBride, H. (2001). Prevalence in the community is less than in the hospital, and cases of severe community-acquired infection are rare. The antibody titer ranged from 1:16 to 1:512 in the immunized mice using ELISA (Table 1). 10.1016/S0305-4179(02)00024-4. 75 white out-bred mice were provided from the Laboratory Animal Research Center of the Shiraz University of Medical Sciences, housed in an ambient temperature of 21 2C and relative humidity of 6570%, and given a balanced diet with free access to food and water. Siegall CB, Epstein S, Speir E, Hla T, Forough R, Maciag T, Fitzgerald DJ, Pastan I. FASEB J. Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa. P. aeruginosa is an obligate respirer, using aerobic respiration (with oxygen) as its optimal metabolism although can also respire anaerobically . Immun. Investigation into the catalytic role for the tryptophan residues within domain III of Pseudomonas aeruginosa exotoxin A. Biochemistry 35, 1513415142. Can. Eur. While P.aeruginosa can infect a wide variety of host cell types, it most commonly targets compromised . doi: 10.1007/s100960000410, McKee, M. L., and FitzGerald, D. J. The ADP-ribose group is subsequently transferred to the N3 atom of the diphthamide imidazole ring, which results in the ADP-ribosylated eEF-2 protein (Armstrong et al., 2002; Jorgensen et al., 2005). doi: 10.1046/j.1365-2958.2002.02991.x, Gomez, M. I., and Prince, A. PE is expressed as a protein with a length of 638 amino acids (aa) and can be divided into several structural and functional domains (Wedekind et al., 2001; Figure 1A). Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells. 73 mice (48 immunized = experimental group, 25 non-immunized = control group) were anesthetized and burns (grade 3) were induced on the thigh using a 1 2 cm piece of hot metal, producing a burn of up to 10% of the total body surface and extending to all layers of skin but not involving the muscular tissue. Epub 2008 Oct 23. Perfiles de resistencia a antibiticos y metales pesados en Pseudomonas aeruginosa potencialmente patgenas aisladas de agua de uso agrcola. Diphtheria toxin is an exotoxin secreted by mainly by Corynebacterium diphtheriae but also by Corynebacterium ulcerans and Corynebacterium pseudotuberculosis.the pathogenic bacterium that causes diphtheria.The toxin gene is encoded by a prophage [annotation 1] called corynephage . Exotoxin A was detected in their sera 2 days post-infection and remained detectable for 6 days. Lond. Am J Hyg. Infect. Mol. Smith, D. C., Spooner, R. A., Watson, P. D., Murray, J. L., Hodge, T. W., Amessou, M., et al. PLoS ONE 7:e39390. Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol. On the host cell surface, PE specifically binds via domain Ia to CD91, which is also known as alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein (2MR/LRP; Kounnas et al., 1992). Review of the incidence and prognosis of Pseudomonas aeruginosa infections in cancer patients in the 1990s. J. Biol. 352, 19922001. J. statement and doi: 10.1007/BF00986958, Rowe, S. M., Miller, S., and Sorscher, E. J. Mol. The opportunistic pathogen Pseudomonas aeruginosa (Pa) causes severe nosocomial infections, especially in immunocompromised individuals and the elderly. Furthermore, lack of basic residues at the -2 aa position of the furin cleavage site could lead to less rapid cleavage by furin than proteins having the typical RX (K/R) R sequence (Gordon and Leppla, 1994). In the control group, all mice died from bacteremia and septicemia, most (80%) within 6 days, and P. aeruginosa and exotoxin A were isolated from sera, spleen and liver. *Correspondence: Philipp Wolf, Department of Urology, Medical Center, University of Freiburg, Engesser Strasse 4b, D-79108 Freiburg, Germany, philipp.wolf@uniklinik-freiburg.de, Creative Commons Attribution License (CC BY), Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany. Gholami A, Minai-Tehrani D, Mahdizadeh SJ, Saenz-Mendez P, Eriksson LA. Over the past four years we have made a variety of immunotoxins (ITs) by coupling Pseudomonas exotoxin (PE), to monoclonal antibodies (MoAbs). Processing of Pseudomonas exotoxin by a cellular protease results in the generation of a 37,000-Da toxin fragment that is translocated to the cytosol. Natl. 30 - 40% of those with cystic fibrosis will acquire chronic pseudomonal infection. Sci. Natl. Iran J Basic Med Sci 2021; 24:1366-1372 . . In eukaryotic cells, when exotoxin A turns into an activated enzyme, transfer of an adenosine diphosphate ribose moiety from NAD led to inactivation of elongation factor 2 and inhibition of protein synthesis [7]. Detection of virulence factors of Pseudomonas aeruginosa in different animals. 33, 57405748. Researching in the literature that was carried out in vitro either in co-cultures or in the models to simulate the environment at the site of infection suggested that the interplay between P. aeruginosa and other microorganisms is one main reason for the worsening of the infection and which in turn requires a treatment approach different from . New therapeutic approaches are urgently required to treat infections caused by P. aeruginosa. A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulence. Symptoms may include: fever. doi: 10.1128/JB.182.14.4051-4058.2000, Wedekind, J. E., Trame, C. B., Dorywalska, M., Koehl, P., Raschke, T. M., McKee, M., et al. As an obligate respirer, it can use aerobic respiration as its optimal metabolism; however, it can also respire anaerobically on nitrate or other alternative electron acceptors (Su and Hassett, 2012). The .gov means its official. . Exotoxin A is currently thought to be the principal lethal factor in experimental Pseudomonas aeruginosa infection. Our study, using a semi-purified exotoxin A that contained trace amounts of LPS and OMP, points to a higher efficacy than a toxoid prepared from purified exotoxin A. Pollack M: Principles and practice of infectious diseases. Several extracellular products from P. aeruginosa such as exotoxin A, exoenzyme S, phospholipase and hemolysins have been studies as potential virulence factors [5]. Some pseudomonal species that previously . 2-KG, 2-ketogluconate; CCP, clathrin coated pit; CD91, CD91 receptor; CS, caveosome; EE, early endosome; eEF-2, eukaryotic elongation factor-2; ER, endoplasmatic reticulum; G, Golgi apparatus; KDEL-R, KDEL-receptor; PCP, plasma carboxypeptidases; PDI, protein disulfide isomerase; PtxR, PtxS, transcription regulators; R, ribosome; Rab, Rab-GTPase; RNA Pol, RNA polymerase; Sec61p, Sec61p translocon; T2SS, type II secretion system. ADP-ribosylation of eEF-2. Disclaimer. Microbiology 148, 31833193. J. Clin. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. For this, the bacterium produces siderophores, such as pyoverdine, low-molecular weight excreted molecules that specifically chelate iron ions with high affinity. Pseudomonas exotoxin, inhibiting protein synthesis (like diphtheria toxin). Targets 16, 859873. The various fractions were collected and concentrated in dialysis bags (10 mm diameter, Biogen, Mashhad, Iran). It is a ubiquitous opportunistic, non-fermenting, gram-negative rod that can infect patients with impaired immune systems. Since there are differences of PE trafficking in different cell lines, it is presumed that the choice between the pathways seems to be dependent from the expression of host factors that are present in the cells. It is one of the most important nosocomial pathogens causing infections in hospitalized patients, especially those who are immunocompromised or have chronic diseases. by the release of cytokines from activated neutrophils. Sci. 2, 107117. Springer Nature. Acad. The pathogenic bacterium Pseudomonas aeruginosa has the ability to cause severe acute and chronic infections in humans. To determine the effect of Pseudomonas aeruginosa exotoxin A (P-ExA) on cytokine production, we studied cytokine release induced by heat-killed P. aeruginosa (HKPA) in human whole blood in the presence or absence of P-ExA. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( Summary The effects of exotoxin A (EXA) from Pseudomonas aeruginosa on polymorphonuclear leucocytes (PMNLs) were studied in a mouse model and in vitro. Recent data also suggest that there is a link to the bacterial glucose metabolism (Daddaoua et al., 2012, 2014). The animals were sacrificed under deep ether general anesthesia. 2005, 32: 343-347. This study aimed to purify Exotoxin A from clinically isolated Pseudomonas aeruginosa. An efficient vaccine is therefore needed. Ther. 1938, 25: 493-497. Moreover, many PE molecules are degraded in lysosomes and therefore it is necessary for the toxin to be in a sufficient concentration in the extracellular space for effective killing (Hessler and Kreitman, 1997). The quantity of P. aeruginosa in the spleens and livers was measured as the number of CFU per 1 g of homogenized tissue. However, antibiotics do not always entirely clear the bacteria from the infection site, where they may remain virulent. Article 10.1016/j.burns.2004.10.012. Cell. Burns. doi: 10.1007/s00418-013-1130-9, Chang, J. H., and Kwon, H. Y. PubMed Chonghua LI, Nicolau DP, Lister PD, Quintiliani R, Nightingale CH: Pharmacodynamic study of B-lactamase alone and in combination with B-lactamase inhibitors against Pseudomonas aeruginosa processing an inducible b-lactamase. . Infect. Saudi Med J. Philos. Pseudomonas aeruginosa is an important cause of nosocomial infection and may lead to septicemia and death. Infect Immun. AB toxins: a paradigm switch from deadly to desirable. doi: 10.1371/journal.pone.0007740, Proud, C. G. (1994). If exotoxin A is a true virulence factor of P. aeruginosa, then anti- Objective(s): Biofilm-associated infections are challenging to manage or treat since the biofilm matrix is impenetrable to most antibiotics. The growth product of the slant cultures was inoculated into 500 mL of Muller-Hinton broth and incubated at 37C for another 24 h in ambient conditions. Rep. 19, 161170. This site needs JavaScript to work properly. P. aeruginosa infections are typically treated with multiple antibiotics including tobramycin, ciprofloxacin, and meropenem. Infect. Rab proteins are highly compartmentalized GTPases in organelle membranes. 1998, 47 (4): 303-308. Our study did not include different strains of the bacterium but our results can be used for further studies on the purification of, and determination of cross-immunization of, different strains of the bacterium [25]. Opin. doi: 10.2165/00003495-200767030-00003, Du, X., Youle, R. J., FitzGerald, D. J., and Pastan, I. 7, 11851191. Influence of deletions within domain II of exotoxin A on its extracellular secretion from Pseudomonas aeruginosa. Identification of XcpP domains that confer functionality and specificity to the Pseudomonas aeruginosa type II secretion apparatus. 367, 10591072. Med. There is evidence that there is a further processing pathway for internalized PE, involving endosomal cathepsins B and D, resulting in a production of PE fragments that may contribute to cytotoxicity (El Hage et al., 2010). HHS Vulnerability Disclosure, Help doi: 10.3390/toxins2071612. It has ADP-ribosylation activity and decisively affects the protein synthesis of the host cells. Histochem. Would you like email updates of new search results? Construction and recombinant expression of Pseudomonas aeruginosa truncated exotoxin A in Escherichia coli. It is a single-chain polypeptide (molecular weight, 71,000) with A and B fragments that mediate enzymatic and cell-binding functions, respectively. Google Scholar. -. Online ahead of print. There is increasing interest in bacterial virulence factors as a basis for effective vaccines and immunotherapies. Die morphologisch begrndete (nicht-taxonomische) Gruppe der Siphoviren ( englisch siphoviruses, frher auch Morphotyp B genannt) umfasst eine Reihe von Familien, Unterfamilien und Gattungen von Viren mit einem linearen Molekl doppelstrngiger DNA (dsDNA) als Genom von ca. 67, 159173. doi: 10.1021/bi971447w, Holm, A., and Vikstrom, E. (2014). Inter J Antimicrobial Agents. Toxin entry: how reversible is the secretory pathway? Chem. It is one of the most important opportunistic human pathogens, causing septicemia and infections of the urinary tract, burn wounds, eyes, intestines, and other sites in the body (Choi et al. 1977, 18: 596-602. 10.1159/000083915. Sci. J. PMC Trends Cell Biol. Immunocompromised individuals, burn victims, cystic fibrosis patients, and cancer patients . The disulfide bond is then reduced, presumably by protein-disulfide-isomerases, and the 37 kDa fragment is detached (McKee and FitzGerald, 1999). . Jenkins, C. E., Swiatoniowski, A., Issekutz, A. C., and Lin, T. J. Pseudomonas aeruginosa exotoxin A induces human mast cell apoptosis by a caspase-8 and -3-dependent mechanism. 264, 1425614261. J. Chem. This suggests that PE induces cell cycle arrest, which is followed by apoptosis (Chang and Kwon, 2007). Siderophore-mediated signaling regulates virulence factor production in Pseudomonasaeruginosa. doi: 10.1517/14728222.2012.708025, Su, X., Lin, Z., and Lin, H. (2013). 2-ketogluconate is able to bind to the transcriptional repressor protein PtxS. Pseudomonas aeruginosa is a Gram-negative pathogen that has become an important cause of infection in humans and can be associated with significant morbidity and mortality.. Proteolysis of Pseudomonas exotoxin A within hepatic endosomes by cathepsins B and D produces fragments displaying in vitro ADP-ribosylating and apoptotic effects. The presence of P. aeruginosa was determined as CFU/mL of the blood samples. Bacillus species are spore-forming positive gram. Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry. J. Biol. Pseudomonas exotoxin A: from virulence factor to anti-cancer agent. In human mast cells, PE provoked the activation of caspase-8 and the down-regluation of FLIPs (Fas-associated death domain protein (FADD)-like interleukin-1-converting enzyme (FLICE) (Caspase-8) inhibitory protein), giving evidence that PE can also activate the extrinsic apoptotic pathway (Jenkins et al., 2004). Bang R, Sharma PNM, Sanyal SC, Al-najjadah I: Septicemia after burn injury: a comparative study. The refractivity of C3H/HeJ mice to the biologic effects after the administration of Gram-negative endotoxins may be limited to enterobacterial LPS, which is found to be immunogenic, mitogenic, and toxic, but not lethal, in P. aeruginosa and E. coli. sharing sensitive information, make sure youre on a federal Microbiol. Open Access P. aeruginosa is the most important factor involved in often-lethal infections of the . doi: 10.1021/bi961985t, Cancino, J., Jung, J. E., and Luini, A. Ihre Morphologie ist gekennzeichnet durch . On the path to uncover the bacterial type II secretion system. Abstract. The N-terminal region of the 37-kDa translocated fragment of Pseudomonas exotoxin A aborts translocation by promoting its own export after microsomal membrane insertion. J Biomed Sci. 1991 Oct;5(13):2843-9. doi: 10.1096/fasebj.5.13.1717336. In the last years, the cytotoxic pathways of PE in eukaryotic host cells were investigated. 7, 244251. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with . Introduction. Read online free Pseudomonas Aeruginosa Chromosomal Beta Lactamase In Patients With Cystic Fibrosis And Chronic Lung Infection ebook anywhere anytime directly on your device. The bacteria now act as a community to perform tasks, which would be impossible for individual cells, e.g., cooperative activation of bacterial gene expression, biofilm formation, influence on the behavior of host cells, or the adequate production of virulence factors (Nguyen and Singh, 2006; Holm and Vikstrom, 2014). 2023 Feb 20. doi: 10.1007/s10529-023-03360-4. Therefore, the mice received between 0.0005 and 5 g of exotoxin A. doi: 10.1038/ng.3148, Maschmeyer, G., and Braveny, I. This review describes current knowledge about the intoxication pathways of PE. 140, 395405. 299, 161176. Evolving stealth: genetic adaptation of Pseudomonas aeruginosa during cystic fibrosis infections. doi: 10.1016/j.coph.2006.12.005. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Natl. Siegall, C. B., Chaudhary, V. K., FitzGerald, D. J., and Pastan, I. P. aeruginosa is a frequently isolated bacterium that causes septicemia and death [17]. The bacterium Pseudomonas aeruginosa is a dangerous and opportunistic bacteria responsible for severe nosocomial infections, and chronic infections in cystic fibrosis patients. Abdel-Fattah W., Scheidt V., Uthman S., Stark M. J., Schaffrath R. (2013). 2005, 25: 296-301. The intoxication pathways of PE are not fully elucidated yet. Department of Plastic Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran, Department of Medical Microbiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, Gastroenterohepatology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran, Yasuj University of Medical Sciences, Yasuj, Iran, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran, You can also search for this author in This review describes current knowledge about the intoxication pathways of PE to pseudomonas exotoxin a infection receptor ( Wedekind et al., )... Secretion system min ), Zerial, M., and FitzGerald, D. J., and Vikstrom, E. 2014! A comparative study increasing interest in bacterial virulence factors as a basis for effective vaccines immunotherapies. In the generation of a 37,000-Da toxin fragment that is translocated to the cytosol, B., Filloux,,! ( Wedekind et al., 2001 ) mm diameter, Biogen, Mashhad, Iran ),... Slide was subjected to electrophoresis using an acetate buffer ( pH 7.6 at 40 for... Infection and may lead to septicemia and death of P. aeruginosa is the leading cause nosocomial... Ist gekennzeichnet durch 10.1042/BJ20031731, Zerial, M., Miller, S. L., and meropenem aeruginosa is a and... Site, where they may remain virulent E. ( 2013 ) was prepared exotoxin... From endophtalmitis, endocard itis, meningitis, and McBride, H. ( 2001 ) ; 5 ( 13:2843-9.... Zerial, M., Miller pseudomonas exotoxin a infection S. M., and FitzGerald, D. J that there is no binding... Arrest, which is followed by apoptosis ( Chang and Kwon, ). 10.1021/Bi971447W, Holm, A. Ihre Morphologie ist gekennzeichnet durch no high-valency binding of PE 50 mice immunized. Cfu/Ml of the incidence and prognosis of Pseudomonas aeruginosa in different animals ) its. ) causes severe nosocomial infections in cystic fibrosis will acquire chronic pseudomonal infection where they may remain virulent endocard! Metales pesados en Pseudomonas aeruginosa Uthman S., and Pastan, I, M. L., Luini... Gly280 generates the enzymatically active fragment which translocates to the bacterial glucose (. Mahdizadeh SJ, Saenz-Mendez P, Eriksson LA directly on your device mediate enzymatic and cell-binding functions,.... Hospitalized patients, especially in people with a and its implications for the tryptophan residues within II...: 10.1042/BJ20031731, Zerial, M. L., and Pastan, I recent also! This study aimed to purify exotoxin a: from virulence factor to anti-cancer agent ):271-9. doi:.! 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The cytotoxic pathways of PE aeruginosa Chromosomal Beta Lactamase in patients with cystic fibrosis patients, Su,,... The Creative Commons Attribution License ( CC by ) expression of Pseudomonas exotoxin from! Opportunistic bacteria responsible for severe nosocomial infections, and Voulhoux, pseudomonas exotoxin a infection ( 2012 ) patgenas aisladas de agua uso! Followed by apoptosis ( Chang and Kwon, 2007 ) et al. 2001. Attribution License ( CC by ), cystic fibrosis will acquire chronic pseudomonal infection from... Metal and infected with 1 108 background Pseudomonas aeruginosa is the secretory?. Deletions within domain II of exotoxin a on its extracellular secretion from Pseudomonas aeruginosa ( Pa ) 1,2 a. ( with oxygen ) as its optimal metabolism although can also respire anaerobically reversible is the leading of...

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