Exploiting the innate immune system to combat multidrug-resistant bacteria

• Infection and Immunotherapy Reseach Group
• Department of Infection and Immunity

In a new study published in the translational journal “eBiomedicine”, researchers from the Infection and Immunotherapy Research group investigated the efficacy of novel complement-activating therapeutics (CoMiX) against the multidrug-resistant bacteria Pseudomonas aeruginosa. In collaboration with the Research Centre for Respiratory Diseases and the Laboratory of Bioimaging and Pathology in France, they have identified two different mechanisms of action that lead to the rapid resolution of an acute infection while limiting harmful chronic inflammation.

Antimicrobial resistance represents a critical threat to human health, as the prevalence of infection in hospitals increases and the efficacy of antibiotics against multidrug-resistant pathogens declines. In particular, Pseudomonas aeruginosa is an opportunistic pathogen responsible for a variety of life-threatening infections in immuno-compromised individuals. Recently it was included in the 2024 priority pathogens list of the World Health Organisation (WHO). In spite of this danger, few promising drug candidates are currently in the clinical pipeline.

The complement system, a part of the innate immune system, plays a key role in host anti-bacterial defences. The Infection and Immunotherapy Research group (INF1) at the Department of Infection and Immunity (DII), led by Dr Carole Seguin-Devaux, has developed antibody-based constructs, called Complement-activating Multimeric immunotherapeutic compleXes (CoMiX), to target and kill the bacterium by activating the complement system.

Using a well-established preclinical model of acute pneumonia, the authors showed that a therapeutic intranasal administration of CoMiX resulted in a reduced local bacterial load, protecting against the lethal infection. They showed that this protection was, in part, associated with increased complement activation and higher production of complement component C3b in the lungs, leading to destruction of the bacteria.

Interestingly, by activating the complement system, CoMiX not only kills bacteria but indirectly promotes the production of the anaphylatoxin C5a in the lungs, driving a transient recruitment and activation of neutrophils, also important for the host anti-bacterial immune response,

says Dr Aubin Pitiot, first author of the study.

Importantly, this proof-of-concept demonstrates that directed-activation of the complement system is a fast and promising therapeutic strategy against P. aeruginosa, an approach which could be extended to other pathogens, and thus opening new therapeutic applications.

Funding

This study was supported by the Luxembourg National Research Fund (FNR), the Ministry of Higher Education and Research of Luxembourg and the COST action CA21145 EURESTOP, as well by institutional grants from INSERM, Tours University and Euro-BioImaging ERIC European grant.