{"title":"铜绿假单胞菌的定向补体杀伤可预防致死性肺炎。","authors":"Aubin Pitiot, Bianca Brandus, Gilles Iserentant, Camille Rolin, Jean-Yves Servais, Delphine Fouquenet, Adélaïde Chesnay, Ludovic Richert, Benoit Briard, Mustapha Si-Tahar, Yves Mely, Patrice Rassam, Jacques Zimmer, Guillaume Desoubeaux, Xavier Dervillez, Carole Seguin-Devaux","doi":"10.1016/j.ebiom.2025.105926","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Multidrug-resistant Pseudomonas aeruginosa raises major clinical concerns due to its capacity to cause a wide-array of infections in individuals with compromised immune defences and to withstand standard-of-care therapeutic treatments. Antibody-based approaches have proven to be efficient in the treatment of diverse infections. Here we propose an innovative approach harnessing the complement at the surface of bacteria for further killing.</p><p><strong>Methods: </strong>We developed two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) targeting the bacterium through a single-chain variable fragment directed against the exopolysaccharide Psl, and carrying one of two different effector functions, Factor H Related protein 1 (FHR1) or a Fc dimer. Each CoMiX was assessed in vitro for their antibacterial activity, and further evaluated in a mouse model of acute pneumonia.</p><p><strong>Findings: </strong>Both CoMiX-FHR1 and CoMiX-Fc effectively deposit C1q (for CoMiX-Fc), C3b, and C5b9 at the surface of multidrug-resistant clinical isolates, promoting their direct killing and/or opsonisation and subsequent phagocytosis for CoMiX-Fc (p < 0.001). Both CoMiX synergise with amikacin and protect epithelial cells against P. aeruginosa-induced cytotoxicity. Importantly, CoMiX administered intranasal to acutely infected mice significantly improve their survival (p < 0.001) by reducing local bacterial burden through the higher induction of C3b (opsonisation) and C5a (neutrophils recruitment and activation) and by decreasing lung inflammation.</p><p><strong>Interpretation: </strong>Our proof-of-concept demonstrates the efficient, direct and indirect killing of P. aeruginosa by the complement, highlighting the therapeutic potential of CoMiX to combat multidrug-resistant bacteria.</p><p><strong>Funding: </strong>Luxembourg National Research Fund, Ministry of Higher Education and Research of Luxembourg, COST action CA21145 EURESTOP, Institut National de la Santé et de la Recherche Médicale, and Tours University.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105926"},"PeriodicalIF":10.8000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466147/pdf/","citationCount":"0","resultStr":"{\"title\":\"Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia.\",\"authors\":\"Aubin Pitiot, Bianca Brandus, Gilles Iserentant, Camille Rolin, Jean-Yves Servais, Delphine Fouquenet, Adélaïde Chesnay, Ludovic Richert, Benoit Briard, Mustapha Si-Tahar, Yves Mely, Patrice Rassam, Jacques Zimmer, Guillaume Desoubeaux, Xavier Dervillez, Carole Seguin-Devaux\",\"doi\":\"10.1016/j.ebiom.2025.105926\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Multidrug-resistant Pseudomonas aeruginosa raises major clinical concerns due to its capacity to cause a wide-array of infections in individuals with compromised immune defences and to withstand standard-of-care therapeutic treatments. Antibody-based approaches have proven to be efficient in the treatment of diverse infections. Here we propose an innovative approach harnessing the complement at the surface of bacteria for further killing.</p><p><strong>Methods: </strong>We developed two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) targeting the bacterium through a single-chain variable fragment directed against the exopolysaccharide Psl, and carrying one of two different effector functions, Factor H Related protein 1 (FHR1) or a Fc dimer. Each CoMiX was assessed in vitro for their antibacterial activity, and further evaluated in a mouse model of acute pneumonia.</p><p><strong>Findings: </strong>Both CoMiX-FHR1 and CoMiX-Fc effectively deposit C1q (for CoMiX-Fc), C3b, and C5b9 at the surface of multidrug-resistant clinical isolates, promoting their direct killing and/or opsonisation and subsequent phagocytosis for CoMiX-Fc (p < 0.001). Both CoMiX synergise with amikacin and protect epithelial cells against P. aeruginosa-induced cytotoxicity. Importantly, CoMiX administered intranasal to acutely infected mice significantly improve their survival (p < 0.001) by reducing local bacterial burden through the higher induction of C3b (opsonisation) and C5a (neutrophils recruitment and activation) and by decreasing lung inflammation.</p><p><strong>Interpretation: </strong>Our proof-of-concept demonstrates the efficient, direct and indirect killing of P. aeruginosa by the complement, highlighting the therapeutic potential of CoMiX to combat multidrug-resistant bacteria.</p><p><strong>Funding: </strong>Luxembourg National Research Fund, Ministry of Higher Education and Research of Luxembourg, COST action CA21145 EURESTOP, Institut National de la Santé et de la Recherche Médicale, and Tours University.</p>\",\"PeriodicalId\":11494,\"journal\":{\"name\":\"EBioMedicine\",\"volume\":\"120 \",\"pages\":\"105926\"},\"PeriodicalIF\":10.8000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466147/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EBioMedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ebiom.2025.105926\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2025.105926","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia.
Background: Multidrug-resistant Pseudomonas aeruginosa raises major clinical concerns due to its capacity to cause a wide-array of infections in individuals with compromised immune defences and to withstand standard-of-care therapeutic treatments. Antibody-based approaches have proven to be efficient in the treatment of diverse infections. Here we propose an innovative approach harnessing the complement at the surface of bacteria for further killing.
Methods: We developed two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) targeting the bacterium through a single-chain variable fragment directed against the exopolysaccharide Psl, and carrying one of two different effector functions, Factor H Related protein 1 (FHR1) or a Fc dimer. Each CoMiX was assessed in vitro for their antibacterial activity, and further evaluated in a mouse model of acute pneumonia.
Findings: Both CoMiX-FHR1 and CoMiX-Fc effectively deposit C1q (for CoMiX-Fc), C3b, and C5b9 at the surface of multidrug-resistant clinical isolates, promoting their direct killing and/or opsonisation and subsequent phagocytosis for CoMiX-Fc (p < 0.001). Both CoMiX synergise with amikacin and protect epithelial cells against P. aeruginosa-induced cytotoxicity. Importantly, CoMiX administered intranasal to acutely infected mice significantly improve their survival (p < 0.001) by reducing local bacterial burden through the higher induction of C3b (opsonisation) and C5a (neutrophils recruitment and activation) and by decreasing lung inflammation.
Interpretation: Our proof-of-concept demonstrates the efficient, direct and indirect killing of P. aeruginosa by the complement, highlighting the therapeutic potential of CoMiX to combat multidrug-resistant bacteria.
Funding: Luxembourg National Research Fund, Ministry of Higher Education and Research of Luxembourg, COST action CA21145 EURESTOP, Institut National de la Santé et de la Recherche Médicale, and Tours University.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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