In lung diseases such as cystic fibrosis (CF), there is a constant interplay between the microbes living in the airways, and the host defense system in the lung and the blood. For the first time in history, CF care is at a tipping point, with new drugs tackling the disease at its very root: these so-called CFTR modulators improve or even restore the CFTR protein that causes CF, not only in the lungs but also in other organs. Many people living with CF (pwCF) who qualify for this therapy experience dramatic improvement in their quality of life and their general and respiratory health. They need less antibiotics and hospital stays, but strangely enough, microbes such as Pseudomonas often remain present in their airways, which leaves many open questions on how to deal with these infections in pwCF on CFTR modulator treatment.

We suspect that CFTR modulation also has effects on the defense cells of pwCF. We will study these effects on white blood cells of pwCF that have already been collected before the start of CFTR modulators, and during this therapy. The groundbreaking new technique we will use, called CITE-seq, allows us to make a complete blueprint of thousands of cells of each study participant, zoom in to the single cell level, and unravel these cells both from the inside and the outside. Those single cells will be compared before and during CFTR modulator therapy within individual patients. To find out whether these changes are really induced by improvement of CFTR function, or just a consequence of a general cooldown of the defense system, we will add control groups of healthy family members of pwCF who are carriers of a CF-causing mutation, and family members who are not carriers of the genetic defect that causes CF. Next, we will check how these defense cells react to confrontation with microbes in the lab.

The defense cells of pwCF have never been examined before in such a thorough way. What makes our project really unique, is that we we will be able to integrate these findings with data from our lab and our collaborators on the changes in the local airway environment itself, and on the microbes living therein. This will eventually lead to a better understanding of the role of CFTR in how our defense system tackles microbial intruders, relevant not only to pwCF but also people living with other chronic lung diseases.