Exit Seminar: Lauren Pugsley

Pathogenesis and antimicrobial susceptibility of Burkholderia cenocepacia in the cystic fibrosis lung

Burkholderia cenocepacia (Bce) is an opportunistic respiratory pathogen that causes devastating and often untreatable infections in people with cystic fibrosis (CF). This clinical challenge is caused by high levels of intrinsic antimicrobial resistance and is compounded by the CF lung environment, where distinct nutritional and environmental characteristics favour the development of chronic Bce infections. We are interested in understanding how these characteristics contribute to antimicrobial susceptibility and Bce pathogenesis. Bce predominantly colocalizes macrophages within the CF lung. I have developed a RAW264.7 macrophage infection model compatible with live-image high-content screening to monitor infection efficiency and intracellular bacterial proliferation over time. This approach has allowed for the first studies on the efficacy of antimicrobials and bioactive compounds against intracellular Bce. This method was used to screen a library of compounds and identify two classes of antibiotics with greater efficacy than the clinical standard at clearing intracellular bacteria. Additionally, the sputum from CF lungs is uniquely acidic. I have identified the cable pilus, Bce’s only characterized adherence organelle, to be dysregulated in acidic pH conditions representative of the CF lung nutritional environment and have begun uncovering its role in pH tolerance and pathogenesis.