Bacterial ‘docking stations’ on cells may explain a Trikafta shortcoming

Effective triple combo therapy not seen to prevent CF lung infections

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A set of lungs are shown struggling to work as intended.

Mutations that cause cystic fibrosis (CF) lead to biochemical changes in lung cells that make it easier for infectious bacteria to stick to the cells, a new study reports.

Findings notably suggest that treatment with Trikafta (ivacaftor/tezacaftor/elexacaftor) did not reverse these changes, which may help to explain why the therapy generally isn’t good at fending off infections.

The study, “Akt-driven TGF-β and DKK1 Secretion Impairs F508del CF Airway Epithelium Polarity,” was published in the American Journal of Respiratory Cell and Molecular Biology.

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Trikafta appears to have little effect on bacterial lung infections

CF is caused by mutations in the gene that provides instructions to make the protein CFTR. Without a functional version of this protein, the body produces abnormally thick and sticky mucus, which drives most disease symptoms. Thick mucus in the lungs provide a fertile breeding ground for bacteria, and chronic lung infections are a common issue for patients.

Trikafta contains a combination of three CFTR modulators, which are therapies that can improve the functionality of the mutated protein in people with CF caused by specific mutations. Studies have shown that the therapy can improve lung function and reduce abnormal mucus in eligible patients.

But available data also suggest that Trikafta has little effect on bacterial lung infections, for reasons that are not clear.

‘‘A significant proportion of people who take this treatment still suffer from residual inflammation and persistent respiratory infections. Understanding the reasons for this is essential if we are to improve patient care,’’ Marc Chanson, PhD, a professor in the department of cell physiology and metabolism at the University of Geneva and a study author, said in a university news release.

In a series of experiments, Chanson and university colleagues demonstrated that lung cells with defective CFTR protein experience changes in biochemical signaling pathways. Specifically, the TGF-beta pathway is overactive, while the WNT pathway is shut down.

These changes in molecular signaling lead to alterations at the surface of lung cells, which creates a sort of “docking station” that makes it easier for infectious bacteria to latch onto, the researchers said. This previously unknown mechanism appears to help in predisposing CF patients to lung infections.

Normalizing affected signaling pathways reduced these cell surface stations

Notably, the researchers found that Trikafta’s use didn’t affect the abnormal molecular pathways or the bacterial “docking stations” on a cell’s surface. This may help to explain why the therapy has minimal impact on infections even as it dramatically alters other aspects of the disease, the scientists said.

“Our data shed new insights into the signaling pathways that fine-tune [cell surface] polarization in primary airway epithelial cells and may provide an explanation to the mitigated efficacy of [Trikafta] on lung infection in people with CF,” the researchers wrote.

Further experiments that manipulated the cells to normalize the TGF-beta and WNT pathways reduced these surface docking stations. These findings could lay the groundwork for new therapies to combat lung infections in CF.

‘‘If we manage to identify a pharmaceutical compound capable of restoring this balance in patients, we could then combine it with the current triple therapy [Trikafta] to increase its efficacy and limit bacterial infections, while reducing its side effects,’’ Chanson said.