Project

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CaOx: applying ecological theory in the fight against lung fungal pathogens

English title CaOx: applying ecological theory in the fight against lung fungal pathogens
Applicant Junier Pilar Eugenia
Number 194701
Funding scheme Bridge - Discovery
Research institution Laboratoire de Microbiologie Institut de Biologie Université de Neuchâtel
Institution of higher education University of Neuchatel - NE
Main discipline Infectious Diseases
Start/End 01.03.2021 - 28.02.2025
Approved amount 1'800'000.00
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All Disciplines (2)

Discipline
Infectious Diseases
Respiratory Diseases

Keywords (4)

Biocontrol; organ-on-a-chip; Lung microbiome; Pulmonary aspergillosis

Lay Summary (French)

Lead
Une nouvelle approche pour lutter contre les champignons pathogènes dans les poumons
Lay summary

Les infections fongiques causent plus de 1,5 million de décès par an mais restent largement négligées. Leur contrôle implique plusieurs défis : un diagnostic rapide est difficile, l'arsenal existant de médicaments est limité et leur efficacité stagne en raison de l'émergence et propagation de résistances. En outre, les infections fongiques sévères sont souvent associées à d'importantes comorbidités. Comme la population à risque augmente, il est urgent de trouver de nouvelles approches visant à moduler les interactions hôte-pathogène. 

Ce projet cible les maladies pulmonaires causées par Aspergillus spp. (champignons filamenteux les plus fréquents chez l'homme), de façon complémentaire à la recherche pharmaceutique traditionnelle, grâce à "l'interférence environnementale". L'objectif est d’exploiter la capacité des bactéries du microbiote pulmonaire à consommer l'acide oxalique requis par Aspergillus spp. lors d'une infection. 

Nous traduirons les résultats obtenus dans des cultures de cellules pulmonaires en un modèle in vivo pour aboutir au stade d'un essai préclinique. Nous établirons en outre une collection de bactéries pulmonaires capables de contrôler Aspergillus spp. par la consommation d'oxalate. Enfin, nous chercherons dans le microbiote des marqueurs précoces de dépistage des patients à haut risque.  Une telle approche est rendue possible par la collaboration de bioinformaticiens, écologistes microbiens et cliniciens, en lien avec deux PME suisses pionnières dans le domaine de la culture cellulaire et des technologies d'organes sur puce. Les résultats attendus obtenus grâce à un large éventail d'approches expérimentales fourniront un ensemble unique d’informations pour la gestion et le traitement personnalisés de l'aspergillose.

Direct link to Lay Summary Last update: 02.02.2021

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Abstract

Fungal infections are estimated to kill more than 1.5 million people worldwide per year. However, the issue of fungal pathogenicity is largely neglected not only by the general public, but also by policy makers and the pharmaceutical industry, despite its impact even in highly resourced countries such as Switzerland. Fighting fungal pathogens poses a series of unique challenges: timely diagnosis is difficult, the existing arsenal of antifungal drugs is limited, and the effectiveness of the current antifungal therapies has plateaued, particularly due to the emergence and spread of resistance. In addition, life threatening fungal infections usually occur in the context of significant co-morbidities. Interactions between commonly used drugs and antifungal therapies, as well as the adverse effects of the latter, are a major challenge in clinical care. Therefore, there is a pressing need to establish novel approaches that reduce our reliance on the discovery of antifungal drugs, allow us to modulate host-fungi interactions, and lead to the discovery of biomarkers for the early identification of patients at risk for fungal infections. This project is based on an entirely new approach, that we have called “environmental interference”, which allows fighting fungal pathogens in a complementary way to traditional drug discovery. This innovative approach exploits the ecology of the lung microbiota, and more concretely, the ability of airway bacteria to consume oxalic acid required by the pathogen during infection, as one of the cornerstones to control the growth of Aspergillus spp. (the most frequently isolated filamentous fungus in humans). This is part of a vision for the management of infectious diseases that is based on the interconnectivity of the host, the pathogen, and the environment. Thus, the strength of this project lies in its potential to bridge fundamental research on soil ecology and the human microbiome, with a highly relevant and timely medical issue: the control of fungal infections. To develop the necessary foundations allowing to implement environmental interference as a therapeutic treatment, we will translate the promising results obtained in artificial lung cell cultures into an in vivo model to reach a status of a pre-clinical trial. Secondly, we will produce a new collection of airway bacteria with the ability to control Aspergillus spp. via oxalate consumption. Finally, we will implement new bioinformatic tools that can be used by clinicians for the screening of the lung microbiome as part of the pipeline for the early identification of at-risk patients. Achieving this in the timeframe of the proposal is feasible by connecting computational prediction with in vitro and in vivo testing in models with complementary biological relevance (3D cell cultures, lung-on-a-chip, and murine systems). Our approach is therefore designed to comply with the fundamental principles of the 3Rs (Replacement, Reduction, Refinement) for conducting ethical research and testing human therapeutic agents. This is possible by connecting bioinformaticians and microbial ecologists, directly with the clinicians at the hospital, and by working closely together with two pioneering Swiss SMEs working in the field of cell culture and organ-on-chip technologies, specifically in physiologically relevant lung models. Validation of infection risk indicators and bacterial biocontrol efficacy across a wide range of experimental approaches will provide a unique toolset for personalized management and treatment of life-threatening aspergillosis.
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