A Pseudomonas aeruginosa Toxin that Hijacks the Host Ubiquitin Proteolytic System

Bomberger, Jennifer M.; Ye, Siying; MacEachran, Daniel P.; Koeppen, Katja; Barnaby, Roxanna; O’Toole, George A.; Stanton, Bruce A.

doi:10.1371/journal.ppat.1001325

Cited by 101 publications

(102 citation statements)

References 50 publications

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“…The PA2394 protein (called CFTR inhibitory factor, Cif ) secreted by P. aeruginosa is also involved in the reduction of CFTR apical membrane expression [41]. A model was then proposed where Cif secretion in P. aeruginosa outer membrane vesicles may reduce USP10-mediated deubiquitination of CFTR and secondarily increase the degradation of CFTR in lysosomes [42]. In agreement with CFTR degradation induced by infection, our results observed in the presence of CHX (fig.…”

Section: Impact Of Infection On Cftr Expressionsupporting

confidence: 84%

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

et al. 2015

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The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells.CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements.A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells.These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors. @ERSpublications Exposure of airway epithelial cell to P. aeruginosa impairs CFTR function, expression and rescue by correctors http://ow.ly/IleTw

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Section: Impact Of Infection On Cftr Expressionsupporting

confidence: 84%

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

et al. 2015

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“…Proteins within P. aeruginosa secreted vesicles have also been reported to play an important role during infection. Typically, vesicles containing cystic fibrosis transmembrane conductance regulator (CFTR)-inhibitory factor (Cif) can reduce chloride secretion by decreasing the apical expression of CFTR and thereby reducing the mucociliary clearance of pathogens (18,19).…”

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confidence: 99%

Pseudomonas aeruginosa Outer Membrane Vesicles Modulate Host Immune Responses by Targeting the Toll-Like Receptor 4 Signaling Pathway

Zhao

Deng

et al. 2013

Infect Immun

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c Bacteria can naturally secrete outer membrane vesicles (OMVs) as pathogenic factors, while these vesicles may also serve as immunologic regulators if appropriately prepared. However, it is largely unknown whether Pseudomonas aeruginosa OMVs can activate inflammatory responses and whether immunization with OMVs can provide immune protection against subsequent infection. We purified and identified OMVs, which were then used to infect lung epithelial cells in vitro as well as C57BL/6J mice to investigate the immune response and the underlying signaling pathway. The results showed that OMVs generated from P. aeruginosa wild-type strain PAO1 were more cytotoxic to alveolar epithelial cells than those from quorum-sensing (QS)-deficient strain PAO1-⌬lasR. The levels of Toll-like receptor 4 (TLR4) and proinflammatory cytokines, including interleukin-1␤ (IL-1␤) and IL-6, increased following OMV infection. Compared with lipopolysaccharide (LPS), lysed OMVs in which the membrane structures were broken induced a weak immune response. Furthermore, expression levels of TLR4-mediated responders (i.e., cytokines) were markedly downregulated by the TLR4 inhibitor E5564. Active immunization with OMVs or passive transfer of sera with a high cytokine quantity acquired from OMV-immunized mice could protect healthy mice against subsequent lethal PAO1 challenges (1.5 ؋ 10 11 CFU). Collectively, these findings indicate that naturally secreted P. aeruginosa OMVs may trigger significant inflammatory responses via the TLR4 signaling pathway and protect mice against pseudomonal lung infection.

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“…The susceptibility to P. aeruginosa infection and lung injury are due either to the toxic effect of a virulence factor or to the severe inflammation resulting from the response to virulence factors, including type III secreted toxins (TTSTs), lipopolysaccharide (LPS), phospholipase C, and flagellin (5,23,46,55,61). The relevance of the different players involved in the pathogenesis of the infection may differ depending on the strain involved.…”

Section: Discussionmentioning

confidence: 99%

Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

et al. 2012

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Toll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulator in vivo under different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused by Pseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acute P. aeruginosa infection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-␥], tumor necrosis factor alpha [TNF-␣], IL-1␤, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense against P. aeruginosa acute lung infection can be improved by blocking IL-1 since exaggerated IL-1␤ production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8 ؊/؊ IL-1RI ؊/؊ double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused by P. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.

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A Pseudomonas aeruginosa Toxin that Hijacks the Host Ubiquitin Proteolytic System

Cited by 101 publications

References 50 publications

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

Pseudomonas aeruginosa Outer Membrane Vesicles Modulate Host Immune Responses by Targeting the Toll-Like Receptor 4 Signaling Pathway

Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection

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