Tobias Grebe, Mithra Tatjana Sarkari, Angelika Cherkaoui, Frieder Schaumburg
{"title":"抑制金黄色葡萄球菌潘顿-瓦伦丁白细胞介素的化合物探索","authors":"Tobias Grebe, Mithra Tatjana Sarkari, Angelika Cherkaoui, Frieder Schaumburg","doi":"10.1007/s00430-024-00803-1","DOIUrl":null,"url":null,"abstract":"<p>The Panton-Valentine leukocidin (PVL) of <i>Staphylococcus aureus</i> is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC<sub>50</sub>) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1β detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC<sub>50</sub> for PVL and were able to suppress IL-1β secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.5000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploration of compounds to inhibit the Panton-Valentine leukocidin of Staphylococcus aureus\",\"authors\":\"Tobias Grebe, Mithra Tatjana Sarkari, Angelika Cherkaoui, Frieder Schaumburg\",\"doi\":\"10.1007/s00430-024-00803-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The Panton-Valentine leukocidin (PVL) of <i>Staphylococcus aureus</i> is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC<sub>50</sub>) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1β detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC<sub>50</sub> for PVL and were able to suppress IL-1β secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.</p>\",\"PeriodicalId\":18369,\"journal\":{\"name\":\"Medical Microbiology and Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Medical Microbiology and Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00430-024-00803-1\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medical Microbiology and Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00430-024-00803-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Exploration of compounds to inhibit the Panton-Valentine leukocidin of Staphylococcus aureus
The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC50) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1β detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC50 for PVL and were able to suppress IL-1β secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.
期刊介绍：
Medical Microbiology and Immunology (MMIM) publishes key findings on all aspects of the interrelationship between infectious agents and the immune system of their hosts. The journal´s main focus is original research work on intrinsic, innate or adaptive immune responses to viral, bacterial, fungal and parasitic (protozoan and helminthic) infections and on the virulence of the respective infectious pathogens.
MMIM covers basic, translational as well as clinical research in infectious diseases and infectious disease immunology. Basic research using cell cultures, organoid, and animal models are welcome, provided that the models have a clinical correlate and address a relevant medical question.
The journal also considers manuscripts on the epidemiology of infectious diseases, including the emergence and epidemic spreading of pathogens and the development of resistance to anti-infective therapies, and on novel vaccines and other innovative measurements of prevention.
The following categories of manuscripts will not be considered for publication in MMIM:
submissions of preliminary work, of merely descriptive data sets without investigation of mechanisms or of limited global interest,
manuscripts on existing or novel anti-infective compounds, which focus on pharmaceutical or pharmacological aspects of the drugs,
manuscripts on existing or modified vaccines, unless they report on experimental or clinical efficacy studies or provide new immunological information on their mode of action,
manuscripts on the diagnostics of infectious diseases, unless they offer a novel concept to solve a pending diagnostic problem,
case reports or case series, unless they are embedded in a study that focuses on the anti-infectious immune response and/or on the virulence of a pathogen.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
