Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia
Aubin Pitiot1, Bianca Brandus2, Gilles Iserentant1
1Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg, Luxembourg.
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.
Insights
New therapeutic complexes (CoMiX) harness the complement system to effectively kill multidrug-resistant Pseudomonas aeruginosa. This innovative approach shows promise for treating severe bacterial infections and improving patient survival rates.
Area of Science:
- Immunology
- Microbiology
- Therapeutics
Background:
- Multidrug-resistant Pseudomonas aeruginosa poses a significant clinical threat, causing infections in immunocompromised individuals and resisting standard treatments.
- Antibody-based therapies are effective for various infections, but new strategies are needed for resistant strains.
- This study explores a novel approach using the complement system for bacterial killing.
Purpose of the Study:
- To develop and evaluate novel immunotherapeutic complexes (CoMiX) for targeting and eliminating multidrug-resistant P. aeruginosa.
- To investigate the mechanism of complement activation and bacterial killing mediated by CoMiX.
- To assess the therapeutic efficacy of CoMiX in a preclinical mouse model of P. aeruginosa pneumonia.
Main Methods:
- Two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) were engineered, targeting Psl on P. aeruginosa and incorporating FHR1 or Fc dimer effector functions.
- In vitro assays assessed antibacterial activity, complement deposition (C1q, C3b, C5b9), and synergistic effects with amikacin.
- An in vivo mouse model of acute pneumonia was used to evaluate CoMiX efficacy in improving survival and reducing bacterial burden and lung inflammation.
Main Results:
- Both CoMiX variants effectively deposited complement components (C1q, C3b, C5b9) on multidrug-resistant P. aeruginosa isolates, leading to direct killing or enhanced phagocytosis.
- CoMiX demonstrated synergy with amikacin and protected epithelial cells from P. aeruginosa-induced cytotoxicity.
- Intranasal administration of CoMiX in mice significantly improved survival by reducing bacterial load, increasing C3b and C5a deposition, and decreasing lung inflammation.
Conclusions:
- The developed CoMiX are a potent proof-of-concept for complement-mediated killing of P. aeruginosa.
- This approach highlights the therapeutic potential of CoMiX in combating challenging multidrug-resistant bacterial infections.
- Harnessing the complement system offers a promising strategy for developing new treatments against resistant pathogens.
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