TY - JOUR
T1 - Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia
AU - Pitiot, Aubin
AU - Brandus, Bianca
AU - Iserentant, Gilles
AU - Rolin, Camille
AU - Servais, Jean Yves
AU - Fouquenet, Delphine
AU - Chesnay, Adélaïde
AU - Richert, Ludovic
AU - Briard, Benoit
AU - Si-Tahar, Mustapha
AU - Mely, Yves
AU - Rassam, Patrice
AU - Zimmer, Jacques
AU - Desoubeaux, Guillaume
AU - Dervillez, Xavier
AU - Seguin-Devaux, Carole
N1 - Funding:
This study was supported by the “Fonds National de la Recherche”
(PRIDE17/11823097/MICROH-DTU, PRIDE19/14254520/I2TRON-
DTU and C22/BM/17380893/PSEUDO), the Ministry of Higher
Education and Research of Luxembourg (LIH GBB 98000005) and a
Short-Term Scientific Mission Grant from the COST action CA21145
EURESTOP (to B.Brandus, C.R, A.P, and C.S.D). This work was also
partially supported by institutional grants from INSERM and Tours
University (to M.S.T), and Euro-BioImaging ERIC European grant for
access to imaging technologies (to Y.M).
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2025/10
Y1 - 2025/10
N2 - 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.
AB - 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.
KW - Complement system
KW - FHR1
KW - Immunotherapy
KW - Multidrug resistance
KW - Pseudomonas aeruginosa
KW - Humans
KW - Pneumonia/microbiology
KW - Anti-Bacterial Agents/pharmacology
KW - Complement System Proteins/immunology
KW - Pseudomonas aeruginosa/immunology
KW - Complement Activation/immunology
KW - Animals
KW - Pseudomonas Infections/immunology
KW - Female
KW - Mice
KW - Phagocytosis
KW - Disease Models, Animal
UR - https://www.scopus.com/pages/publications/105015989015
UR - https://pubmed.ncbi.nlm.nih.gov/40961506/
U2 - 10.1016/j.ebiom.2025.105926
DO - 10.1016/j.ebiom.2025.105926
M3 - Article
C2 - 40961506
AN - SCOPUS:105015989015
SN - 2352-3964
VL - 120
JO - EBioMedicine
JF - EBioMedicine
M1 - 105926
ER -