Cystic fibrosis triple therapy does not eliminate bacterial infection predisposal in vitro

Key takeaways:

• Elexacaftor/tezacaftor/ivacaftor is an approved treatment for children and adults with cystic fibrosis.
• Development of docking stations on the respiratory tract is tied to bacterial infection susceptibility.

It is known that persons with cystic fibrosis are more susceptible to infections; however, the impact of elexacaftor/tezacaftor/ivacaftor therapy on this susceptibility has not been well studied yet.

In a study published in American Journal of Respiratory Cell and Molecular Biology, researchers explored whether triple therapy stopped docking stations, a mechanism tied to bacterial infections, from forming in those with cystic fibrosis (CF).

The researchers found that the treatment did not stop this phenomenon and that there is a difference in cell signaling pathways between healthy cells and CF cells.

To learn more about docking stations, the study’s findings and future research, Healio spoke with Marc Chanson, PhD, full professor in the department of cell physiology and metabolism at the University of Geneva and member of the Geneva Inflammation Research Centre, and Mehdi Badaoui, PhD, research and teaching fellow in the department of cell physiology and metabolism at the University of Geneva.

Healio: In what ways has triple therapy helped patients with CF? What are some limitations of this therapy?

Badaoui and Chanson: For a majority of persons with cystic fibrosis (pwCF), the mutant CFTR protein does not reach the plasma membrane to function as an ion channel. The elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy corrects this phenotype by restoring CFTR channel localization and function.

Multiple clinical trials reported significant improvements in lung function, nutritional status and pulmonary exacerbation frequency in pwCF 1 year after ETI initiation. Despite this success, there is still lack of therapy for very young children and for 10% of pwCF harboring CFTR variants that are not targeted by ETI. In addition, recent studies revealed that lung infection persists for some patients even months after treatment initiation.

Healio: What are “docking stations?” How do these contribute to infections?

Badaoui and Chanson: Docking stations describe the abnormal localization at the surface of the airway epithelium of fibronectin, a component of the extracellular matrix, and of its beta-1 integrin receptor, normally expressed at the basolateral membrane of epithelial cells. Both proteins are long-time known to be substrates for bacteria binding, including P. aeruginosa, which is the main threat for pwCF.

Importantly, we observed that this phenotype was not corrected by short-term exposure of primary cultures of CF airway epithelial cells to ETI. We suggest that the ectopic localization of these docking stations contributes to the sensibility of pwCF for chronic infection and represents a potential cause of the persistent infection under ETI therapy.

Healio: Could you explain the difference you found in cell signaling pathways between healthy cells and CF cells? Why are these pathways significant when considering the development of infections?

Badaoui and Chanson: The airway epithelium has the possibility to repair, to regenerate, after injury caused, for example, by infection. Two major cell-signaling pathways are known to contribute to the airway epithelium regeneration, namely the TGF-beta and Wnt pathways. The on/off regulation of these, and other, pathways during repair allows restoring the airway epithelium integrity, thus its physical barrier function.

In CF, it appears that this on/off regulation is altered, regenerating an airway epithelium with enhanced TGF-beta signaling and reduced Wnt signaling. Inhibiting TGF-beta pathway or re-activating Wnt pathway in CF prevented the apical deposition of fibronectin to the surface of the airway epithelium, thus eliminating the docking stations.

Healio: How do you restore the balance between the TGF-beta and Wnt cell signaling pathways, reducing the development of these docking stations? If this is unknown, how do you suspect balance can be restored?

Badaoui and Chanson: Our study was performed in vitro, on human primary airway epithelial cells isolated from pwCF and on CF human cell lines grown at the air-liquid interface to mimic the respiratory tract environment. Pharmacological modulators were applied at one dose for a short period.

In vivo, the on/off regulatory interplay between both pathways is continuously taking place during the regeneration process. This means that it would be necessary to determine the kinetics of activation/inactivation of both pathways to modulate them precisely and specifically for re-establishing the right balance at the right time. We do not know how to achieve this at this stage of the research.

Healio: Researchers recently found that a zinc transport protein may help decrease bacterial infections in CF. How could this information and your findings be used in the development of future CF therapies?

Badaoui and Chanson: There are multiple causes to explain bacterial infections in CF, from defective airway epithelium regeneration, reduced mucociliary clearance and mucus clogging, antimicrobial peptides inactivation to defective innate immune response. What is the contribution of all these defects in a given timeframe is not really known. Combinatorial treatments with molecules targeting multiple aspects of the CF phenotype and adapted to an individual may be a possible strategy.

Healio: What do you have planned for future research?

Badaoui and Chanson: Targeting signaling pathways is always challenging because they are involved in many cell functions, and thus compromising specificity of action. We are currently investigating why the CF epithelium expose these docking stations at the surface and more specifically what regulates the altered polarity of the CF airway epithelial cells. We believe that understanding by which mechanism fibronectin is relocated to the apical side of the epithelium may help to design more specific approaches to prevent the formation of bacterial docking stations.

The development of anti-adhesive agents is also very promising for preventing infection at an early stage. The binding of microbes to the airway epithelium surface is decisive for the initiation of bacterial growth, airways’ colonization and antimicrobial resistance. Blocking the interaction between the bacteria and the CF docking stations is another interesting approach that we are investigating with our close collaborators, Christian van Delden, MD, and Thilo Köhler, PhD, at the Medical Faculty of the University of Geneva. This is of particular concern given the growing crisis of antibiotic resistance.

For more information:

Marc Chanson, PhD, can be reached at marc.chanson@unige.ch.

Mehdi Badaoui, PhD, can be reached at mehdi.badaoui@unige.ch.

References:

• Cystic fibrosis: Why infections persist despite therapy. https://www.unige.ch/medecine/en/public-outreach/media/cystic-fibrosis-why-infections-persist-despite-therapy. Published April 4, 2024. Accessed April 11, 2024.
• Idris T, et al. Am J Respir Cell Mol Biol. 2024;doi:10.1165/rcmb.2023-0408OC.