PROJECT SUMMARY Why patients with cystic fibrosis (CF) continue to suffer from chronic bacterial infections despite new medications that improve CF transmembrane conductance regulator (CFTR) function is unknown. The objective of this proposal is to define how new triple combination highly effective CFTR modulator therapy (HEMT) alters CF phagocytic cell function. The rationale underlying this proposal is that our prior work demonstrates that CF macrophages and neutrophils are integral to the inability of patients with CF to clear bacterial infections through several dysfunctional mechanisms. Many of these mechanisms are only partially amenable to treatment with currently available CFTR modulators. The central hypothesis is that CF phagocytic cell function is dependent on functional CFTR, can be restored by HEMT, and correlates with clinical responses. The central hypothesis will be tested by pursuing three specific aims: 1) Determine whether HEMT changes functional CFTR in CF macrophages and neutrophils; 2) Assess HEMT-treated macrophage and neutrophil functional responses to infection; and 3) Correlate individual clinical responses with phagocytic cell function. We will pursue these aims using unique models and assays that include human macrophages and neutrophils and association with well-characterized clinical data. The proposed research is significant because a precise understanding of how CF macrophage and neutrophil function is regulated by HEMT would allow novel, personalized treatment approaches to infection in CF and other diseases. The expected outcome of this work will establish a mechanistic framework to enable us to target and correct defective killing of bacteria in CF. The long-term goal is to develop therapeutics that modulate host immune responses in CF patients to mitigate chronic infection and inflammation. Ultimately, we will translate this new knowledge into a new treatment paradigm that uses innovative host-directed therapies to combat bacterial infections.