Pseudomonas aeruginosa elastase cleaves a C-terminal peptide from human thrombin that inhibits host inflammatory responses

Plas, Mariena J. A. van der; Bhongir, Ravi K. V.; Kjellström, Sven; Siller, Helena; Kasetty, Gopinath; Mörgelin, Matthias; Schmidtchen, Artur

doi:10.1038/ncomms11567

Cited by 64 publications

(73 citation statements)

References 41 publications

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“…5). As previously reported, subsequent proteolysis leads to formation of smaller TCPs of about 2 kDa with antiendotoxic functions (10,14,15) (Fig. 5).…”

Section: Discussionmentioning

confidence: 53%

“…5). Interestingly, P. aeruginosa "hijacks" this mechanism by release of bacterial elastase, which cleaves out a TCP of 21 aa, thereby enabling modulation and circumvention of host responses (14). In many aspects, such TCPs act as "classical" host defense peptides like LL-37 (26), which also binds to LPS, leading to inhibition of NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, clearance and control of endotoxins are critical to maintaining a robust antibacterial response while maintaining control of inflammatory responses. Thrombin-derived C-terminal peptides (TCPs) of roughly 2 kDa [e.g., FYTHVFRLKKWIQKVIDQFGE, HVFRLKKWIQKVIDQFGE (12)(13)(14)], which are present in wounds, frequently form helices upon LPS binding and exert antiendotoxic functions in vitro and in vivo (10,12). From a therapeutic standpoint, a prototypic thrombin-derived peptide, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE) has been shown to protect against Pseudomonas aeruginosa sepsis, mainly via reduction of both systemic cytokine responses and excessive coagulation (12,15).…”

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confidence: 99%

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Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Petrlová

Hansen

Plas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria. In silico molecular modeling using atomic resolution and coarse-grained simulations corroborates our experimental observations, altogether indicating increased aggregation through LPS-mediated intermolecular contacts between clusters of TCP molecules. Upon bacterial aggregation, recombinantly produced TCPs induce permeabilization of Escherichia coli and phagocytic uptake. TCPs of about 11 kDa are present in acute wound fluids as well as in fibrin sloughs from patients with infected wounds. We noted aggregation and colocalization of LPS with TCPs in such fibrin material, which indicates the presence of TCP-LPS aggregates under physiological conditions. Apart from identifying a function of proteolyzed thrombin and its fragments, our findings provide an interesting link between the coagulation system, innate immunity, LPS scavenging, and protein aggregation/amyloid formation.aggregation | thrombin | lipopolysaccharides | host defense peptides

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“…5). As previously reported, subsequent proteolysis leads to formation of smaller TCPs of about 2 kDa with antiendotoxic functions (10,14,15) (Fig. 5).…”

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Petrlová

Hansen

Plas

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, elastases cleave complement components and also elastin, collagen, IgG, mucin, and surfactant proteins to escape from phagocytosis and clearance [46]. Pseudomonas proteases can mimic the activity of neutrophil elastase by cleaving peptides from host thrombin that inhibits inflammatory responses [47]. …”

Section: Qs-regulated Factors That Impact P Aeruginosa Communities Amentioning

confidence: 99%

Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of <b><i>Pseudomonas aeruginosa</i></b> Infections

Turkina

Vikström

2018

J Innate Immun

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Cell-to-cell signaling via small molecules is an essential process to coordinate behavior in single species within a community, and also across kingdoms. In this review, we discuss the quorum sensing (QS) systems used by the opportunistic pathogen Pseudomonas aeruginosa to sense bacterial population density and fitness, and regulate virulence, biofilm development, metabolite acquisition, and mammalian host defense. We also focus on the role of N-acylhomoserine lactone-dependent QS signaling in the modulation of innate immune responses connected together via calcium signaling, homeostasis, mitochondrial and cytoskeletal dynamics, and governing transcriptional and proteomic responses of host cells. A future perspective emphasizes the need for multidisciplinary efforts to bring current knowledge of QS into a more detailed understanding of the communication between bacteria and host, as well as into strategies to prevent and treat P. aeruginosa infections and reduce the rate of antibiotic resistance.

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“…In addition, P. aeruginosa elastase is known to lead to degradation of pro-inflammatory cytokines such as IL-6 or IL-8 to avoid host immune defense (37). A recent report also showed that thrombin cleaved by P. aeruginosa elastase attenuated TLR-mediated pro-inflammatory responses (38). In correlation with these studies, our results clearly demonstrate that P. aeruginosa proteases degrade inflammasome components including caspase-1 and ASC, as well as pro-inflammatory cytokines in the extracellular space (Figure 9).…”

Section: Discussionmentioning

confidence: 97%

Bacterial Secretant from Pseudomonas aeruginosa Dampens Inflammasome Activation in a Quorum Sensing-Dependent Manner

et al. 2017

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Inflammasome signaling can contribute to host innate immune defense against bacterial pathogens such as Pseudomonas aeruginosa. However, bacterial evasion of host inflammasome activation is still poorly elucidated. Quorum sensing (QS) is a bacterial communication mechanism that promotes coordinated adaptation by triggering expression of a wide range of genes. QS is thought to strongly contribute to the virulence of P. aeruginosa, but the molecular impact of bacterial QS on host inflammasome defense is completely unknown. Here, we present evidence that QS-related factors of the bacterial secretant (BS) from P. aeruginosa can dampen host inflammasome signaling in mouse bone marrow-derived macrophages. We found that BS from QS-defective ΔlasR/rhlR mutant, but not from wild-type (WT) P. aeruginosa, induces robust activation of the NLRC4 inflammasome. P. aeruginosa-released flagellin mediates this inflammasome activation by ΔlasR/rhlR secretant, but QS-regulated bacterial proteases in the WT BS impair extracellular flagellin to attenuate NLRC4 inflammasome activation. P. aeruginosa-secreted proteases also degrade inflammasome components in the extracellular space to inhibit the propagation of inflammasome-mediated responses. Furthermore, QS-regulated virulence factor pyocyanin and QS autoinducer 3-oxo-C12-homoserine lactone directly suppressed NLRC4- and even NLRP3-mediated inflammasome assembly and activation. Taken together, our data indicate that QS system of P. aeruginosa facilitates bacteria to evade host inflammasome-dependent sensing machinery.

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Pseudomonas aeruginosa elastase cleaves a C-terminal peptide from human thrombin that inhibits host inflammatory responses

Cited by 64 publications

References 41 publications

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of <b><i>Pseudomonas aeruginosa</i></b> Infections

Bacterial Secretant from Pseudomonas aeruginosa Dampens Inflammasome Activation in a Quorum Sensing-Dependent Manner

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