Investigating Highly Effective Modulator Treatment of Cystic Fibrosis on Bacteria Infection of the Airway Epithelium

Cystic Fibrosis (CF) is a genetically inherited disease with over 2,000 known variants in the Cystic Fibrosis

Transmembrane Regulator (CFTR) gene. Respiratory deterioration is the leading cause of mortality in CF

patients. The introduction of Highly Effective Modulator Therapy (HEMT) has marked a significant

milestone, leading to overall improved lung function and extended survival in CF patients. However,

despite some patients reporting positive outcomes with HEMT, many continue to experience persistent

bacterial infections, lung inflammation.

In previous research on Human Airway Epithelial Cells (HAECs), we found that the CF airway epithelium

is prone to infections due to luminal bacterial docking stations composed of ectopic β1-integrin and

Fibronectin-1 (FN-1) expression, suggesting a loss of apicobasal polarity. This abnormality is driven in part

by abnormal activity of the Wnt/β-catenin pathway. We observed that HEMT fails to reverse the increased

apical deposition of FN-1, a protein to which the bacteria Pseudomonas aeruginosa (Pa) adheres. However,

the molecular regulatory networks sustaining high FN-1 apical secretion in presence of HEMT are still

unknown. Additionally, CF patients with identical CFTR variants often exhibit varying responses to HEMT,

leading to the hypothesis that individual differences in epigenetic profiles could significantly influence

HEMT efficacy. We will utilize in vitro Calu-3 cells to research biological functions linked to the non-

canonical Wnt pathway. Furthermore, single cell multiome sequencing will be performed on primary

HAECs cultures to gather epigenomic and genomic data from the same individuals.