Bacterial Nucleotidyl Cyclase Inhibits the Host Innate Immune Response by Suppressing TAK1 Activation

He, Chenxi; Zhou, Yunting; Liu, Feng; Liu, Haipeng; Tan, H.; Jin, Shouguang; Wu, Weihui; Ge, Baoxue

doi:10.1128/iai.00239-17

Cited by 26 publications

(28 citation statements)

References 67 publications

(80 reference statements)

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“…The precise role of ExoY in P. aeruginosa infection still remains largely unclear. ExoY has been proposed to alter cell integrity leading to loss of endothelial cell barrier integrity (11,17), although more recent results suggest that it may also contribute to dampen the host innate immune responses (15,16). Inactivation of these ExoY functions may be beneficial at certain stages or forms of the bacterial infection.…”

Section: Terminus Of P Aeruginosa Exoymentioning

confidence: 99%

“…In cell culture experiments, ExoY causes the formation of gaps between endothelial cells, thus increasing permeability of the endothelial monolayer in lungs (11,12) (yet these effects were not observed by other groups (13,14)). Very recently, two groups independently demonstrated that ExoY activity also leads to the inhibition of the host immune responses by suppressing the activation of TAK1 and decreasing the production of IL-1␤ (15,16). In vivo in animal models, ExoY was shown to cause severe lung damage in rats (17) and mice (18).…”

mentioning

confidence: 99%

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The extreme C terminus of the Pseudomonas aeruginosa effector ExoY is crucial for binding to its eukaryotic activator, F-actin

Belyy

Santecchia²,

Renault

et al. 2018

Journal of Biological Chemistry

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Edited by Velia M. FowlerBacterial nucleotidyl cyclase toxins are potent virulence factors that upon entry into eukaryotic cells are stimulated by endogenous cofactors to catalyze the production of large amounts of 35-cyclic nucleoside monophosphates. The activity of the effector ExoY from Pseudomonas aeruginosa is stimulated by the filamentous form of actin (F-actin). Utilizing yeast phenotype analysis, site-directed mutagenesis, functional biochemical assays, and confocal microscopy, we demonstrate that the last nine amino acids of the C terminus of ExoY are crucial for the interaction with F-actin and, consequently, for ExoY's enzymatic activity in vitro and toxicity in a yeast model. We observed that isolated C-terminal sequences of P. aeruginosa ExoY that had been fused to a carrier protein bind to F-actin and that synthetic peptides corresponding to the extreme ExoY C terminus inhibit ExoY enzymatic activity in vitro and compete with the full-length enzyme for F-actin binding. Interestingly, we noted that various P. aeruginosa isolates of the PA14 family, including highly virulent strains, harbor ExoY variants with a mutation altering the C terminus of this effector. We found that these naturally occurring ExoY variants display drastically reduced enzymatic activity and toxicity. Our findings shed light on the molecular basis of the ExoY-F-actin interaction, revealing that the extreme C terminus of ExoY is critical for binding to F-actin in target cells and that some P. aeruginosa isolates carry C-terminally mutated, low-activity ExoY variants.

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Section: Terminus Of P Aeruginosa Exoymentioning

confidence: 99%

mentioning

confidence: 99%

The extreme C terminus of the Pseudomonas aeruginosa effector ExoY is crucial for binding to its eukaryotic activator, F-actin

Belyy

Santecchia²,

Renault

et al. 2018

Journal of Biological Chemistry

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“…During this early innate immune response, the stage is set for an effective mount of a host immune response against P. aeruginosa [ 24 , 25 ]. It has been documented that ExoY lowers concentrations of TNF and IL-1β after infection of rat lungs or epithelial cells, respectively [ 26 , 27 ]. Again, our data indicate that this dampening of the proinflammatory immune response within the infected organ already starts at 2-4 h after infection.…”

Section: Discussionmentioning

confidence: 99%

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

Kloth

Schirmer

Munder

et al. 2018

Toxins

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The effector protein Exotoxin Y (ExoY) produced by Pseudomonas aeruginosa is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear. Here, we used an acute airway infection model in mice to address the role of ExoY in lung infection. In infected lungs, a dose-dependent phenotype of infection with bacteria-expressing ExoY was mirrored by haemorrhage, formation of interstitial oedema in alveolar septa, and infiltration of the perivascular space with erythrocytes and neutrophilic granulocytes. Analyses of the infection process on the cellular and organismal level comparing infections with Pseudomonas aeruginosa mutants expressing either nucleotidyl cyclase-active or -inactive ExoY revealed differential cytokine secretion, increased prevalence of apoptosis, and a break of lung barrier integrity in mice infected with cyclase-active ExoY. Notably, of all measured cyclic nucleotides, only the increase of cyclic UMP in infected mouse lungs coincides temporally with the observed early pathologic changes. In summary, our results suggest that the nucleotidyl cyclase activity of ExoY can contribute to P. aeruginosa acute pathogenicity.

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“…In addition, Exo Y impairs recovery of the endothelial cell barrier, decreasing migration, proliferation, and lung repair [151]. Exo Y, somewhat paradoxically, inhibits rather than induces pro-inflammatory cytokine and chemokine production in macrophages, as such decreasing secretion of IL-1β, IL-6, TNF, and of the chemokine IL-8/CXCL8 [154,155].…”

Section: Exotoxin Y (Exo Y)mentioning

confidence: 99%

Impact of Bacterial Toxins in the Lungs

Lucas

Hadizamani

Gonzales

et al. 2020

Toxins

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Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung’s innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.

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Bacterial Nucleotidyl Cyclase Inhibits the Host Innate Immune Response by Suppressing TAK1 Activation

Cited by 26 publications

References 67 publications

The extreme C terminus of the Pseudomonas aeruginosa effector ExoY is crucial for binding to its eukaryotic activator, F-actin

The extreme C terminus of the Pseudomonas aeruginosa effector ExoY is crucial for binding to its eukaryotic activator, F-actin

The Role of Pseudomonas aeruginosa ExoY in an Acute Mouse Lung Infection Model

Impact of Bacterial Toxins in the Lungs

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