Cystic fibrosis: Physiopathology and phenogenomics

Harriet Corvol & Loïc Guillot
Team leader(s) : Harriet Corvol   &   Loïc Guillot
Administrative contact : Erwan Leforestier

Saint-Antoine Hospital - Kourilsky Building – 6th floor
184, rue du Faubourg Saint-Antoine - 75012 Paris - France

Group leaders
Professors, Lecturers, Researchers, Clinicians
Post-docs, Contract researchers, Emeritus, Volunteering
Engineers, Technicians
PhD candidates, MSc students

Cystic fibrosis (CF) is a genetic disease caused by variants of the gene coding for the chloride channel CFTR (Cystic Fibrosis Transmembrane conductance Regulator). More than 2000 CFTR variants have been described, the most common being F508del. Although CF is a monogenic disease, a large phenotypic diversity is observed in people with CF (pwCF) carrying the same CFTR variants. In addition to environmental factors, modifying genes contribute to this variability. This disease affects several organs such as the pancreas, liver, intestine, and more severely the lungs. In the airways, the absence of a functional CFTR leads to impaired mucociliary clearance, chronic infections, exacerbated inflammation, and lung tissue destruction. Pulmonary disease remains the main cause of morbidity and mortality in CF.

Three main axes of research on CF are studied in our laboratory: modifying genes, therapeutic strategies targeting RNAs, and the response of bronchial epithelial cells following microbial infection.

Modifier genes
Genotype/phenotype association
Our goal is to identify and understand the function of genes and variants on the phenotypic variability of pwCF. Our team is coordinating a national study on CF modifier genes (4900 French pwCF included: ~75% of the French CF population, participation of all 47 CF expert centers. We recently identified: clinical (Boelle et al. Hepatology. 2019) and genetic (SERPINA1; Boelle et al. Genet Med. 2019) risk factors for severe CF liver disease; several genes associated with lung infection (TNF, DCTN4, SLC9A3, CAV2: Mesinele et al. J Cyst Fibros. 2022) and interpatient variability in response to CFTR modulators (ivacaftor/SLC26A9: Corvol et al. Front Pharmacol. 2018; lumacaftor/ivacaftor/SLC6A14: Mesinele et al. J Pers Med. 2022). We also performed functional genetic studies to evaluate the impact of the identified genes such as FAM13A (Corvol et al. J Cyst Fibros. 2018). We are currently looking for new modifier genes associated to P. aeruginosa infection and liver disease in particular.
In collaboration with North American teams, we participated in the development of new biostatistical models to analyze modifier genes (e.g. Sun et al. HGG Adv. 2022) and identified (GWAS and candidate gene analyses) genes associated with lung disease severity (MUC4/MUC20, SLC9A3, HLA Class II, AGTR2/SLC6A14, EHF/APIP) (e.g. Polineni et al. Am J Respir Crit Care Med. 2018) and diabetes in CF (SLC26A9, TCF7L2) (e.g. Lin et al. Genet Med. 2021).

Functional study of SLC6A14
At the functional level, we are studying SLC6A14, identified as a modifier gene of the lung disease severity of pwCF (Corvol et al. Nat Commun. 2015). We wish to understand how this gene, which encodes an amino acid transporter, modulates CF lung disease (Ruffin et al. Cell Mol Life Sci. 2020). We have already demonstrated that its inhibition induces a decrease in the bronchial epithelia repair (Mercier et al. Front Mol Biosci. 2022). We are now studying its potential involvement in the regulation of the response to P. aeruginosa infection and the maintenance of bronchial epithelial integrity via the regulation of nitric oxide production.

Therapeutic strategy targeting RNAs
Our goal is to propose a therapy independent of CFTR variants. We are developing an alternative strategy to that targeting CFTR RNAs (Sonneville et al. Am J Pathol. 2015; Bardin et al, Front Pharmacol, 2018; Bardin et al, Med Sci, 2018) and targeting all pwCF, whatever the CFTR variants. Thus, we have developed a molecule preventing the binding of a microRNA that inhibits the ANO1/TMEM16A chloride channel (6 international patents). In cell models, this molecule is able to correct different deregulated parameters in CF such as chloride ion secretion, mucociliary clearance and tissue repair (Sonneville et al. Nat Commun. 2017). We have also shown that this therapeutic approach improves the survival of mice homozygotes for the F508del variant. Our goal being to bring this molecule in the clinic, we have created the startup Anoat Therapeutics in 2023. In parallel, we have also shown that some miRNAs participated in the exacerbation of the pulmonary inflammation of pwCF (Bardin et al. J Pathol. 2018). This work is ongoing to find new therapeutic approaches based on our previous experience.

Study of the response of bronchial epithelial cells following infection
The acquisition of a microbial infection is a key step in the progression of the severity of CF lung disease. This is particularly critical in children under five years old who develop chronic bacterial lung infections by P. aeruginosa. Fungal infections have significantly increased in recent decades. Aspergillus fumigatus is the most common filamentous fungus isolated from respiratory secretions of people with underlying chronic respiratory diseases such as CF and COPD. We are also working on viral infections, and in particular by SARS-CoV-2 since the start of the pandemic. The objective is to better understand the interactions between bronchial epithelial cells (BEC) and these pathogens, particularly P. aeruginosa, A. fumigatus and SARS-CoV-2

P. aeruginosa
We are studying the role of proteins called Septins (SEPT) in the interaction of BECs with P. aeruginosa. In other contexts, these cytoskeletal proteins are involved in the maintenance of epithelial integrity (permeability and repair), the inflammatory response, host-pathogen interactions and pathogen internalization. Modulation of the expression, localization and/or activity of SEPT could have important consequences on the response to respiratory infections in pwCF. We are developing new therapeutic strategies against P. aeruginosa by studying the effect of antimicrobial peptides and by characterizing the role of the EXOY toxin of this bacterium.

A. fumigatus
We are looking for cellular receptors and fungal ligands involved in the interaction between BECs and A. fumigatus. In this context, we have shown that the fungal lectin FleA expressed by A. fumigatus spores induces an inhibition of filament formation on BECs (Richard et al. Sci Rep, 2018). We are also investigating the epigenetic mechanisms of the innate immune memory of BECs. Indeed, their exposure to a bacterial component, such as the flagellin of P. aeruginosa, modifies their inflammatory response to pathogens encountered during a second infection occurring at a distance (Bigot et al. Front Immunol. 2020; Bigot et al. J Fungi. 2022). Finally, the limited anti-fungal therapeutic arsenal and the emergence of resistance to azoles in A. fumigatus also led us to sudy antimicrobial peptides.

We aim to determine and understand the susceptibility of pwCF to SARS-CoV-2 infection. In a national observational study (MUCOVID), we showed that pwCF are not more frequently infected by SARS-CoV-2 than the general population (Corvol et al. J Clin Med. 2020). Nevertheless, pwCF with more advanced lung disease develop more severe COVID-19 (Corvol et al. Clin Inf Dis. 2022). In parallel with these clinical studies, we showed that SARS-CoV-2 infection can be promoted by pre-exposure to P. aeruginosa flagellin (Ruffin et al. Front immunol 2021).

St. Antoine Hospital

Kourilsky Building
34 rue Crozatier - 75012 Paris

Sorbonne Université Medicine
Saint-Antoine Site
27 rue Chaligny - 75012 Paris

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