Understanding Chronic Lung Infections after Correcting the Basic Cystic Fibrosis Defect

Abstract

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the first drug that can correct the physiologic defect was approved. These drugs, called “CFTR modulators”, offer great hope to people with CF, as many clinical measures of health improve, including lung function, nutritional status, and frequency of disease flares. Unfortunately, despite marked improvements in overall health, there are hints that modulators cannot restore patients to full health. Early studies indicate chronic bacterial infections persist in many patients, and these patients’ lungs remain inflamed. This is important because before modulators, chronic infection and inflammation were the main drivers of lung disease progression and death. The failure of modulators to resolve these pathologies suggests that lung disease may continue to progress in persistently infected patients taking CFTR modulators. The goal of my thesis work was to better understand persistent post-modulator lung infections. In chapter 2, I describe a method we developed to enumerate and quantify the bacterial strains present in a pool of thousands of cultured isolates or directly from the sputum of people with CF. This method enables new questions to be addressed regarding the frequency of multi-strain infections and the degree of strain turnover during infections before and after modulator therapy. In chapter 3, we test an eradication protocol that combined intensive antibiotic treatment with modulator therapy. While antibiotics have not previously been able to clear chronic infections, we hypothesized modulator-induced changes in the lung environment could make antibiotics more effective. Finding that infections generally persisted after combined treatment inspired me to develop a deeper understanding of the causes of persistent infection after modulators. In chapter 4, we used bronchoscopy to sample many lung regions within each subject to identify characteristics of regions which remain persistently infected compared to those that clear infection. Results from this study suggest that structural lung damage may allow bacterial pathogens to persist, and show persistent infection is strongly associated with levels of inflammation after modulators. The work presented in this thesis reveals difficulties in eradicating chronic infection after modulators, and sheds light on the underlying causes of this difficulty.