A dual-action peptide-containing hydrogel targets wound infection and inflammation

Puthia, Manoj; Butrym, Marta; Petrlová, Jitka; Strömdahl, Ann‐Charlotte; Andersson, Madelene Å; Kjellström, Sven; Schmidtchen, Artur

doi:10.1126/scitranslmed.aax6601

Cited by 111 publications

(118 citation statements)

References 54 publications

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“…Bioluminescence from the mice was detected and quantified using Living Image 4.0 Software (PerkinElmer Life Sciences). Fifteen minutes before the IVIS imaging, mice were intraperitoneally given 100 l of D-luciferin (150 mg/kg body weight) (14).…”

Section: Mouse Inflammation Modelmentioning

confidence: 99%

“…In vivo bacterial infection was imaged by measuring bioluminescence in anesthetized mice using IVIS imaging and the data obtained were analyzed using Living Image 4.0 Software (PerkinElmer Life Sciences). 5 to 6 mice per treatment group were used (14).…”

Section: Mouse Model Of Subcutaneous Infectionmentioning

confidence: 99%

“…A, THP-1-XBlue-CD14 cells were treated with rTCP96, LPS from E. coli (Ec), or a combination of both. rTCP96 yielded a significant reduction of activation of NF-B/AP-1(14). **, p Յ 0.01; ****, p Յ 0.0001.…”

mentioning

confidence: 97%

“…We have previously shown that proteolysis of thrombin by human neutrophil elastase (HNE) leads to the formation of thrombin-derived C-terminal peptides (TCPs) of roughly 2 kDa (8), which are present in wound fluids (9,10) and have been demonstrated to exert antiendotoxic functions in vitro and in vivo (8,(10)(11)(12)(13)(14). Apart from these smaller fragments, proteolysis of thrombin by HNE also generates 11-kDa TCPs that are present in wounds.…”

mentioning

confidence: 99%

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Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Petrlova

Petruk

Huber

et al. 2020

Journal of Biological Chemistry

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Thrombin-derived C-terminal peptides (TCPs), including a major 11-kDa fragment (TCP96), are produced through cleavage by human neutrophil elastase and aggregate lipopolysaccharide (LPS) and the Gram-negative bacterium Escherichia coli. However, the physiological roles of TCP96 in controlling bacterial infections and reducing LPS-induced inflammation are unclear. Here, using various biophysical methods, in silico molecular modeling, microbiological and cellular assays, and animal models, we examined the structural features and functional roles of recombinant TCP96 (rTCP96) in the aggregation of multiple bacteria and the Toll-like receptor (TLR) agonists they produce. We found that rTCP96 aggregates both Gram-negative and Gram-positive bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and their cell-wall components LPS, lipid A, and lipoteichoic acid (LTA). The Gram-negative bacteria E. coli and P. aeruginosa were particularly sensitive to aggregation-induced bacterial permeabilization and killing. As a proof of concept, we show that rTCP96 reduces LPS-induced NF-κB activation in human monocytes, as well as in mouse models of LPS-induced subcutaneous inflammation. Moreover, in a mouse model of subcutaneous inoculation with P. aeruginosa, rTCP96 reduced bacterial levels. Together, these results link TCP-mediated aggregation of endotoxins and bacteria in vitro to attenuation of inflammation and bacterial levels in vivo.

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Section: Mouse Inflammation Modelmentioning

confidence: 99%

Section: Mouse Model Of Subcutaneous Infectionmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Petrlova

Petruk

Huber

et al. 2020

Journal of Biological Chemistry

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“…In an experimental animal model, we wanted to simulate a situation of localized endotoxin induced inflammation. In previous models, we utilized doses of 100 µg LPS injected subcutaneously, a dose level which yielded a robust and significant LPS response (13). In this modified model, similar to the strategy described above on the THP-1 cells, we employed low, threshold levels comprising 2 µg LPS which were injected subcutaneously with or without 5 µg S protein.…”

Section: Effects Of Sars-cov-2 S Protein On Endotoxin Responses In Anmentioning

confidence: 99%

SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

Petruk

Puthia

Petrlova

et al. 2020

Preprint

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ABSTRACTThere is a well-known and established link between high lipopolysaccharide (LPS) levels in blood and the metabolic syndrome (MS). MS is a risk factor for developing severe COVID-19 and acute respiratory distress syndrome (ARDS). Here we define an interaction between SARS-CoV-2 Spike (S) protein and LPS and its link to aggravated inflammation in vitro and in vivo. Electrophoresis under native conditions demonstrated that SARS-CoV-2 S protein binds to Escherichia coli LPS, forming high molecular weight aggregates. Microscale thermophoresis analysis further defined the interaction, having a KD of ~47 nM, similar to the observed affinity between LPS and the human receptor CD14. Moreover, S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) and cytokine responses in monocytic THP-1 cells and human blood, respectively. In an experimental model of localized inflammation, employing NF-κB reporter mice and in vivo bioimaging, S protein in conjunction with LPS significantly increased the inflammatory response when compared with S protein and LPS alone. Apart from providing information on LPS as a ligand for S protein, our results are of relevance for studies on comorbidities involving bacterial endotoxins, such as the MS, or co-existing acute and chronic infections in COVID-19 patients.

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A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Wang

Jiang

et al. 2022

Advanced Biology

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including pneumonia, sepsis and meningitis, and other chronic infections. [1] Novel antibiotics are the most favorable choice, however, the lack of innovative antibiotic development coupled with the frequent emergence of resistant strains may send us back to a preantibiotic era. Increasing evidence suggests that the excessive use of broad-spectrum antibiotics is associated with the risk of many metabolic and inflammatory diseases and some potential diseases related to the disruption of microbiota. [2][3] The rising prevalence of multidrug-resistant and highly virulent strains increases the urgent need for new therapies independent of antibacterial activity.S. aureus produces diverse exotoxins to facilitate its colonization and spreading during infection, and one of the most well-characterized exotoxins is Hla, a typical β-barrel pore-forming cytotoxin expressed by almost all clinical isolates. [4] Hla plays indispensable role in the pathogenesis of invasive infections, phagosome escape, and partially the triggering of the immune response. [5] Hla-induced activation of a disintegrin and metalloproteinase 10 is a critical mechanism of barrier disruption that greatly contributes to the pathogenesis of lethal S. aureus infections by enabling effective spreading. [6] Hla pore-dependent activation of NOD-like receptor protein 3 inflammasome is a successful example of pathogens exploiting host inflammatory signaling by enhancing the pathogenesis of severe S. aureus infection via inducing necrosis. [7] Moreover, Hla is exploited to manipulate adaptive immunity against S. aureus, suppressing the antigen-specific memory T cell response by disturbing DC-T cell crosstalk. [8] Notably, the pore formation activity of Hla is required for these cellular events as the inactive mutant H35L retains the ability to bind the membrane while impaired pore formation fails to act in these cases. The critical role of Hla in S. aureus pathogenesis renders it a developing therapeutic target for virulence-specific strategies aiming to attenuate the pathogenicity of S. aureus rather than directly kill bacteria.Host innate immune response is the first line of defense against S. aureus infection, promoting bacterial clearance and limiting the inciting injury of infection and systemic spreading through neutrophil chemotaxis, phagocytosis and inflammation. [9] However, inflammation is a double-edged sword. In most Antibiotic resistance is the greatest challenge for the treatment of Staphylococcus aureus (S. aureus) infection under the global antibiotic resistance crisis. With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual-action inhibitor of Hla, a pore-forming virulence determinant particularly important for S. aureus pathogenicity and Toll-like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen-associated molecular patterns. Amentoflavone treatment conferred effective protec...

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A dual-action peptide-containing hydrogel targets wound infection and inflammation

Cited by 111 publications

References 54 publications

Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

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