Multiple <i>Pseudomonas</i> species secrete exolysin‐like toxins and provoke Caspase‐1‐dependent macrophage death

Basso, Pauline; Wallet, Pierre; Elsen, Sylvie; Soleilhac, Emmanuelle; Henry, Thomas; Faudry, Eric; Attrée, Ina

doi:10.1111/1462-2920.13841

Cited by 37 publications

(35 citation statements)

References 92 publications

(172 reference statements)

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“…When indicated triton X100 (Sigma) at 1% (v/v) was added at the end of the kinetics to further control cell death/viability. Area under the curve were computed using Prism software (GraphPad) to obtain a single quantitative readout of the full kinetics as recently described [ 64 ]. Gliotoxin (Enzo Pharma) and Nigericin (Sigma) were used at 5 μM, the latter after a 3 h priming with LPS at 100 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Wallet¹,

Benaoudia²,

Mosnier³

et al. 2017

PLoS Pathog

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Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners.

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Section: Methodsmentioning

confidence: 99%

IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Wallet¹,

Benaoudia²,

Mosnier³

et al. 2017

PLoS Pathog

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“…Active caspase-1 induces the maturation of the pro-IL-1β into IL-1β. Caspase-1 also provokes the rupture of macrophage plasma membrane by a process called pyroptosis, releasing massive quantities of pro-inflammatory IL-1β in the surrounding environment [ 20 ] ( Figure 2 B). Therefore, similarly to T3SS-positive strains, ExlA-secreting bacteria are capable of triggering inflammasome activation and pro-inflammatory cell death of macrophages in vitro.…”

Section: Caspase-1 Dependent Death Of Macrophagesmentioning

confidence: 99%

“…This genetic organization is conserved in all clonal outliers sequenced to date. Bioinformatics analysis performed on all genomes available in the Pseudomonas database [ 10 ] revealed the presence of exlBA genes in several Pseudomonas species, including P. putida , P. entomophila , P. protegens and P. fluorescens [ 20 ]. Here we bring insights regarding the structural and functional features of this novel toxin acquired by some multi-resistant P. aeruginosa strains.…”

Section: Introductionmentioning

confidence: 99%

Exolysin Shapes the Virulence of Pseudomonas aeruginosa Clonal Outliers

Reboud

Basso

Maillard

et al. 2017

Toxins

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Bacterial toxins are important weapons of toxicogenic pathogens. Depending on their origin, structure and targets, they show diverse mechanisms of action and effects on eukaryotic cells. Exolysin is a secreted 170 kDa pore-forming toxin employed by clonal outliers of Pseudomonas aeruginosa providing to some strains a hyper-virulent behaviour. This group of strains lacks the major virulence factor used by classical strains, the Type III secretion system. Here, we review the structural features of the toxin, the mechanism of its secretion and the effects of the pore formation on eukaryotic cells.

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“…Recently we found that other Pseudomonas species, such as Pseudomonas putida, Pseudomonas protegens and Pseudomonas entomophila, express ExlA-like toxins which are responsible for pyroptotic death of macrophages (52). Orthologs of vfr and cyaB genes are present in these species, inferring a common regulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

cAMP and Vfr Control Exolysin Expression and Cytotoxicity of Pseudomonas aeruginosa Taxonomic Outliers

et al. 2018

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The two-partner secretion system ExlBA, expressed by strains of belonging to the PA7 group, induces hemorrhage in lungs due to disruption of host cellular membranes. Here we demonstrate that the genes are controlled by a pathway consisting of cAMP and the virulence factor regulator (Vfr). Upon interaction with cAMP, Vfr binds directly to the promoter with high affinity (equilibrium binding constant [] of ≈2.5 nM). The and expression was diminished in the Vfr-negative mutant and upregulated with increased intracellular cAMP levels. The Vfr binding sequence in the promoter was mutated, resulting in reduced cytotoxicity of the mutant, showing that Vfr is required for the expression during intoxication of epithelial cells. Vfr also regulates function of type 4 pili previously shown to facilitate ExlA activity on epithelial cells, which indicates that the cAMP/Vfr pathway coordinates these two factors needed for full cytotoxicity. As in most strains, the adenylate cyclase CyaB is the main provider of cAMP for Vfr regulation during both growth and eukaryotic cell infection. We discovered that the absence of functional Vfr in the reference strain PA7 is caused by a frameshift in the gene and accounts for its reduced cytotoxicity, revealing the conservation of ExlBA control by the CyaB-cAMP/Vfr pathway in taxonomic outliers. The human opportunistic pathogen provokes severe acute and chronic human infections associated with defined sets of virulence factors. The main virulence determinant of taxonomic outliers is exolysin, a membrane-disrupting pore-forming toxin belonging to the two-partner secretion system ExlBA. In this work, we demonstrate that the conserved CyaB-cAMP/Vfr pathway controls cytotoxicity of outlier clinical strains through direct transcriptional activation of the operon. Therefore, despite the fact that the type III secretion system and exolysin are mutually exclusive in classical and outlier strains, respectively, these two major virulence determinants share similarities in their mechanisms of regulation.

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Multiple Pseudomonas species secrete exolysin‐like toxins and provoke Caspase‐1‐dependent macrophage death

Cited by 37 publications

References 92 publications

IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Exolysin Shapes the Virulence of Pseudomonas aeruginosa Clonal Outliers

cAMP and Vfr Control Exolysin Expression and Cytotoxicity of Pseudomonas aeruginosa Taxonomic Outliers

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