Amentoflavone attenuates Listeria monocytogenes pathogenicity through an LLO‐dependent mechanism
Background and Purpose L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identif...
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Published in | British journal of pharmacology Vol. 179; no. 14; pp. 3839 - 3858 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Blackwell Publishing Ltd
01.07.2022
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Subjects | |
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Abstract | Background and Purpose
L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection.
Experimental Approach
Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO‐mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined.
Key results
Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose‐dependently reduced L. monocytogenes‐induced cell injury in an LLO‐dependent manner. In the Caco‐2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO‐dependent manner, and inhibition was attributed to ability to block perforation‐associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate.
Conclusions and Implications
Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection. |
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AbstractList | L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection.BACKGROUND AND PURPOSEL. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection.Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO-mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined.EXPERIMENTAL APPROACHHaemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO-mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined.Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose-dependently reduced L. monocytogenes-induced cell injury in an LLO-dependent manner. In the Caco-2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO-dependent manner, and inhibition was attributed to ability to block perforation-associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate.KEY RESULTSAmentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose-dependently reduced L. monocytogenes-induced cell injury in an LLO-dependent manner. In the Caco-2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO-dependent manner, and inhibition was attributed to ability to block perforation-associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate.Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection.CONCLUSIONS AND IMPLICATIONSAmentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection. Background and PurposeL. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection.Experimental ApproachHaemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO‐mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined.Key resultsAmentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose‐dependently reduced L. monocytogenes‐induced cell injury in an LLO‐dependent manner. In the Caco‐2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO‐dependent manner, and inhibition was attributed to ability to block perforation‐associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate.Conclusions and ImplicationsAmentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection. Background and Purpose L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection. Experimental Approach Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO‐mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined. Key results Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose‐dependently reduced L. monocytogenes‐induced cell injury in an LLO‐dependent manner. In the Caco‐2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO‐dependent manner, and inhibition was attributed to ability to block perforation‐associated K+ efflux and Ca2+ influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate. Conclusions and Implications Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection. L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of L. monocytogenes infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of L. monocytogenes infection. Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO-mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with L. monocytogenes was examined. Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose-dependently reduced L. monocytogenes-induced cell injury in an LLO-dependent manner. In the Caco-2 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by L. monocytogenes in an LLO-dependent manner, and inhibition was attributed to ability to block perforation-associated K efflux and Ca influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate. Amentoflavone reduced the pathogenicity of L. monocytogenes by specifically inhibiting LLO pore formation, and this may represent a potential treatment for L. monocytogenes infection. |
Author | Can, Zhang Xuming, Deng Tingting, Wang Tianqi, Fang Xinyu, Wang Xue, Shen Jianfeng, Wang |
Author_xml | – sequence: 1 givenname: Wang surname: Tingting fullname: Tingting, Wang organization: Jilin University – sequence: 2 givenname: Fang surname: Tianqi fullname: Tianqi, Fang organization: Jilin University – sequence: 3 givenname: Wang surname: Xinyu fullname: Xinyu, Wang organization: Jilin University – sequence: 4 givenname: Zhang surname: Can fullname: Can, Zhang organization: Jilin University – sequence: 5 givenname: Shen surname: Xue fullname: Xue, Shen organization: Jilin University – sequence: 6 givenname: Deng surname: Xuming fullname: Xuming, Deng email: Dengxm@jlu.edu.cn organization: Jilin University – sequence: 7 givenname: Wang orcidid: 0000-0001-8311-0894 surname: Jianfeng fullname: Jianfeng, Wang email: wjf927@jlu.edu.cn organization: Jilin University |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35229287$$D View this record in MEDLINE/PubMed |
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Keywords | amentoflavone Listeria monocytogenes listeriolysin O (LLO) inhibitor immune response barrier function |
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Notes | Funding information Wang Tingting and Fang Tianqi contributed equally to this work. National Natural Science Foundation of China, Grant/Award Numbers: 81861138046, NO.31902321, 31902321, 32172912; Fundamental Research Funds for the Central Universities, Grant/Award Number: 2020‐JCXK‐39 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
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L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved... L. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic... Background and PurposeL. monocytogenes remain a leading cause of foodborne infection. Listeriolysin O (LLO), an indispensable virulence determinant involved in... |
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SubjectTerms | amentoflavone barrier function Calcium efflux Calcium influx Cell injury Cytotoxicity Herbal medicine Immune response Infections Inflammation Listeria monocytogenes Listeriolysin O listeriolysin O (LLO) inhibitor Pathogenicity Surface plasmon resonance Therapeutic targets Virulence |
Title | Amentoflavone attenuates Listeria monocytogenes pathogenicity through an LLO‐dependent mechanism |
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