Pseudomonas aeruginosa exotoxin T induces potent cytotoxicity against a variety of murine and human cancer cell lines

Goldufsky, Joe; Wood, Stephen; Hajihossainlou, Behnam; Rehman, Tooba; Majdobeh, Omar; Kaufman, Howard L.; Ruby, Carl E.; Shafikhani, Sasha H.

doi:10.1099/jmm.0.000003-0

Cited by 18 publications

(17 citation statements)

References 73 publications

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“…Cytotoxicity Measurement by Time-lapse VideomicroscopyCytotoxicity measurement by time-lapse videomicroscopy was performed as described previously (21,22). Briefly, HeLa cells were grown in DMEM without phenol red with (for transfection studies) or without antibiotics (for infection studies) for 24 h. These cells were then transfected with the indicated expression vectors as described (11) or infected with the indicated strains as described (13).…”

Section: Methodsmentioning

confidence: 99%

Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity

Wood¹,

Goldufsky²,

Bello³

et al. 2015

Journal of Biological Chemistry

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Background:The GAP domain of ExoT induces apoptosis in epithelial cells, but the mechanism underlying GAP-induced apoptosis remains unknown. Results: GAP domain activates JNK1/2, causes cytochrome c release, and activates caspase-9 and caspase-3. Conclusion: GAP domain of ExoT induces intrinsic apoptosis in epithelial cells. Significance: The GAP and the ADPRT domains make ExoT into a potent cytotoxin, capable of inducing different forms of apoptosis.

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Section: Methodsmentioning

confidence: 99%

Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity

Wood¹,

Goldufsky²,

Bello³

et al. 2015

Journal of Biological Chemistry

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“…Dissecting the mechanisms by which Pseudomonas aeruginosa Exotoxin T (ExoT) induces apoptosis in target epithelial cells is an area of investigation in our laboratory (Goldufsky et al, 2015; Shafikhani et al, 2008a; Wood et al, 2015a; Wood et al, 2015b). In a recent study (Wood et al, 2015a), we demonstrated that ExoT, by ADPribosylating CrkI adaptor protein, disrupts focal adhesion and interferes with integrin/FAK/p130Cas/β-catenin survival signaling, inducing anoikis apoptosis in epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and Compensatory Proliferation Signaling Are Coupled by CrkI-Containing Microvesicles

et al. 2017

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Summary Apoptosis has been implicated in Compensatory Proliferation Signaling (CPS), whereby dying cells induce proliferation in neighboring cells as a means to restore homeostasis. The nature of signaling between apoptotic cells and their neighboring cells remains largely unknown. Here we show that a fraction of apoptotic cells produce and release CrkI-containing microvesicles (distinct from exosomes and apoptotic bodies), which induce proliferation in neighboring cells upon contact. We provide visual evidence of CPS by videomicroscopy. We show that purified vesicles in vitro and in vivo are sufficient to stimulate proliferation in other cells. Our data demonstrate that CrkI inactivation by ExoT bacterial toxin or by mutagenesis blocks vesicle formation in apoptotic cells and inhibits CPS, thus uncoupling apoptosis from CPS. We further show that c-Jun amino-terminal kinase (JNK) plays a pivotal role in mediating vesicle-induced CPS in recipient cells. CPS could have important ramifications in diseases that involve apoptotic cell death.

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“…In order to evaluate the impact of high (80 %) and low/ standard (30 %) FiO 2 therapies on SSI, we injected either saline (mock) or 5Â10 6 CFU of PA103 bacteria -[a wildtype P. aeruginosa strain described previously (Ohman et al, 1980;Wood et al, 2013;Goldufsky et al, 2015a, b)] -into biceps femoris muscle, using a rat muscle surgical model for infection that we described previously (Kroin et al, 2015) (for more detailed protocol, see Methods). Immediately after surgery and infection, animals were exposed to either high 80 % FiO 2 or 30 % low (standard) FiO 2 for 5 h, as described in Methods.…”

Section: Resultsmentioning

confidence: 99%

“…In line with the importance of P. aeruginosa infection in SSI, we and others have demonstrated that P. aeruginosa uses a variety of virulence mechanisms to inhibit wound healing both in vivo and in vitro in order to propagate its favourite niche 'the wound' (Garrity-Ryan et al, 2004;Shafikhani & Engel, 2006;Zhao et al, 2010;Goldufsky et al, 2015b;Wood et al, 2015a, b). The strain of P. aeruginosa used in this study was PA103, which we and others have described previously (Shafikhani & Engel, 2006;Wood et al, 2013;Goldufsky et al, 2015a, b). Cultures were propagated in tryptic soy broth.…”

Section: Surgical Infection Modelmentioning

confidence: 91%

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Perioperative high inspired oxygen fraction therapy reduces surgical site infection with Pseudomonas aeruginosa in rats

Goldufsky

Gupta

et al. 2016

Journal of Medical Microbiology

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Surgical site infection (SSI) remains one of the most important causes of healthcare-associated infections, accounting for~17 % of all hospital-acquired infections. Although short-term perioperative treatment with high fraction of inspired oxygen (FiO 2 ) has shown clinical benefits in reducing SSI in colorectal resection surgeries, the true clinical benefits of FiO 2 therapy in reducing SSI remain unclear because randomized controlled trials on this topic have yielded disparate results and inconsistent conclusions. To date, no animal study has been conducted to determine the efficacy of short-term perioperative treatments with high (FiO 2 >60 %) versus low (FiO 2 <40 %) oxygen in reducing SSI. In this report, we designed a rat model for muscle surgery to compare the effectiveness of short-term perioperative treatments with high (FiO 2 =80 %) versus a standard low (FiO 2 =30 %) oxygen in reducing SSI with Pseudomonas aeruginosaone of the most prevalent Gram-negative pathogens, responsible for nosocomial SSIs. Our data demonstrate that 5 h perioperative treatment with 80 % FiO 2 is significantly more effective in reducing SSI with P. aeruginosa compared to 30 % FiO 2 treatment. We further show that whilst 80 % FiO 2 treatment does not affect neutrophil infiltration into P. aeruginosa-infected muscles, neutrophils in the 80 % FiO 2 -treated and infected animal group are significantly more activated than neutrophils in the 30 % FiO 2 -treated and infected animal group, suggesting that high oxygen perioperative treatment reduces SSI with P. aeruginosa by enhancing neutrophil activation in infected wounds.

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Pseudomonas aeruginosa exotoxin T induces potent cytotoxicity against a variety of murine and human cancer cell lines

Cited by 18 publications

References 73 publications

Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity

Pseudomonas aeruginosa ExoT Induces Mitochondrial Apoptosis in Target Host Cells in a Manner That Depends on Its GTPase-activating Protein (GAP) Domain Activity

Apoptosis and Compensatory Proliferation Signaling Are Coupled by CrkI-Containing Microvesicles

Perioperative high inspired oxygen fraction therapy reduces surgical site infection with Pseudomonas aeruginosa in rats

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