Exoenzyme S from <i>Pseudomonas aeruginosa</i> induces apoptosis in T lymphocytes

Bruno, Tony F.; Woods, Donald E.; Mody, Christopher H.

doi:10.1002/jlb.67.6.808

Cited by 25 publications

(24 citation statements)

References 70 publications

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“…Nonetheless, it remains a partially elucidated picture how the "on and off" switch of ExoS secretion in susceptible human host correlates with the progression of the P. aeruginosa infection. In recent years, increasing numbers of studies, both in vitro or in vivo, describe apoptosis induction by P. aeruginosa (17,23,36,38,46,77,89); some of the studies identified a variety of apoptosis-inducing factors from the bacterium (2,7,8,34,47,50,88). Bruno et al (7) and we (50) first reported ExoS as one of these factors.…”

Section: Discussionmentioning

confidence: 90%

“…We intended to further dissect signaling pathways involving ExoSmediated apoptosis. P. aeruginosa possesses a large array of virulence factors that can cause host cell toxicity to certain extend (2,7,8,34,47,50,60,67,75,88,93,95); at the same time, it has not been demonstrated conclusively whether ExoSdependent apoptosis induction coincides with necrosis-like cell death resulting from the diverse effects on cellular components by ExoS or whether apoptosis is secondary to that event. It is therefore important to determine whether the ExoS protein alone is sufficient to induce apoptosis in host cells independent of other bacterial virulence components.…”

Section: Transiently Expressed Exos Induces Apoptosis In Hela Cellsmentioning

confidence: 99%

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Expression ofPseudomonas aeruginosaToxin ExoS Effectively Induces Apoptosis in Host Cells

et al. 2006

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Pseudomonas aeruginosa is an opportunistic bacterial pathogen that primarily infects immunocompromised individuals and patients with cystic fibrosis. Invasive strains of P. aeruginosa are known to induce apoptosis at a high frequency in HeLa cells and in many other cell lines, a process that is dependent on the ADPribosylation (ADPRT) activity of a type III secreted protein ExoS. In our previous report, it was proposed that P. aeruginosa secreting ExoS, upon infection, shuts down host cell survival signal pathways by inhibiting ERK1/2 and p38 activation, and it activates proapoptotic pathways through activation of JNK1/2, leading ultimately to cytochrome c release and activation of caspases. In this study, we demonstrate that the expression of ExoS in HeLa cells by eukaryotic expression vector effectively caused apoptosis in an ADPRT activitydependent manner, indicating that ExoS alone is sufficient to trigger apoptotic death of host cells independent of any other bacterial factors. By expressing an EGFP-ExoS fusion protein, we were able to directly correlate the death of HeLa cells with the presence of intracellular ExoS and further proved the dependence of this process on both JNK activation and mitochondrial proapoptotic event. The cellular pathway responsible for the ExoS-induced cytotoxicity appears to be well conserved, since the expression of the ADPRT-competent ExoS also induced rapid cell death in the Drosophila melanogaster S2 cell lines. The presented study not only highlights the ability of ExoS ADPRT to modulate host cell signaling, eventually leading to apoptosis, but also establishes ExoS as a valuable tool, in principle, for the elucidation of apoptosis mechanisms.

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Section: Discussionmentioning

confidence: 90%

Section: Transiently Expressed Exos Induces Apoptosis In Hela Cellsmentioning

confidence: 99%

Expression ofPseudomonas aeruginosaToxin ExoS Effectively Induces Apoptosis in Host Cells

et al. 2006

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“…Recently, Usher and colleagues have reported induction of neutrophil apoptosis by Pseudomonas pyocyanin and suggested it as a potential mechanism of persistent infection (41). In addition, a variety of cells, including macrophages, epithelial cells, fibroblasts, and T cells, have been shown to be targets of P. aeruginosa-induced apoptosis (2,12,18). The present study showed that macrophages and neutrophils are susceptible, while epithelial cells are resistant, to 3-oxo-C 12 -HSL-induced cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

ThePseudomonas aeruginosaAutoinducerN-3-Oxododecanoyl Homoserine Lactone Accelerates Apoptosis in Macrophages and Neutrophils

et al. 2003

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Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C 12 -HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C 12 -HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C 12 -HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C 12 -HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.

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“…Exoenzyme-S-induced activation of T cells is neither dependent upon nor inhibited by ADP-ribosyltransferase activity, and this activity is present in exoenzyme S from both purified and recombinant sources (7). Further, we have found that activation by exoenzyme S induces T-cell apoptosis (6). The current studies were performed to determine whether this T-cell activation culminates in the induction of cytokines that have the potential of influencing immunoinflammatory responses or whether apoptosis precludes cytokine transcription.…”

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confidence: 93%

Pseudomonas aeruginosaExoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines

Epelman

Bruno

Neely³

et al. 2000

Infect Immun

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Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orchestrated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeruginosa mitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1␣ [IL-1␣], IL-1␤, IL-6, IL-8, MIP-1␣, MIP-1␤, MCP-1, RANTES, and I-309), modest transcription of immunoregulatory cytokines (IL-10 and IL-12p40), and weak transcription of Th1 cytokines (IL-2 and gamma interferon). The response occurred early and subsided without evolving over time. These data suggest that cells responding to exoenzyme S would rapidly express proinflammatory cytokines and chemokines that may contribute to pulmonary inflammation in cystic fibrosis.Virtually all cystic fibrosis (CF) patients are colonized by Pseudomonas aeruginosa, and 90% of those that are colonized die as a result of lung damage (11). One of the hallmarks of the lung damage in CF is an ineffective inflammatory response that results in severe neutrophil-mediated pulmonary damage and an inability to clear the organisms. P. aeruginosa contributes to the lung damage by the production of virulence factors; one of the most important virulence factors, exoenzyme S, has been shown to induce pulmonary damage in animal models (17,29,35), and increased levels of exoenzyme S correlate with human disease (18, 36). The cytotoxicity of exoenzyme S for epithelial cells follows both contact-dependent type III translocation into eukaryotic target cells and contact-independent type III secretion, suggesting two mechanisms of cellular activation: intracellular and extracellular (15,34,35). We have recently described an additional activity: extracellular exoenzyme S is mitogenic for T cells, inducing tremendous T-cell activation (5-7). Exoenzyme-S-induced activation of T cells is neither dependent upon nor inhibited by ADP-ribosyltransferase activity, and this activity is present in exoenzyme S from both purified and recombinant sources (7). Further, we have found that activation by exoenzyme S induces T-cell apoptosis (6). The current studies were performed to determine whether this T-cell activation culminates in the induction of cytokines that have the potential of influencing immunoinflammatory responses or whether apoptosis precludes cytokine transcription.Immunoinflammatory responses are orchestrated by cytokines, and T-cell mitogens and superantigens are potent stimuli for cytokine production from T cells, monocytes, and macrophages (2, 3). In CF there is a misdirected or dysregulated response, since there is a chronic and exuberant immunoinflammatory response without clearance of the pathogen. This response may be a result of altered cytokine induction that includes decreased secretion of the anti-inflammatory cytokine interleukin-10 (IL-10) (13, 28) with concordant increases in proinflammatory cy...

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Exoenzyme S from Pseudomonas aeruginosa induces apoptosis in T lymphocytes

Cited by 25 publications

References 70 publications

Expression ofPseudomonas aeruginosaToxin ExoS Effectively Induces Apoptosis in Host Cells

Expression ofPseudomonas aeruginosaToxin ExoS Effectively Induces Apoptosis in Host Cells

ThePseudomonas aeruginosaAutoinducerN-3-Oxododecanoyl Homoserine Lactone Accelerates Apoptosis in Macrophages and Neutrophils

Pseudomonas aeruginosaExoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines

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