Colin Sheehan

Research Summary

Pseudomonas aeruginosa is a Gram-negative pathogen responsible for a variety of opportunistic infections. In the aiway, the bacterium uses a wide array of toxins and virulence factors to evade host immunity and cause disease in patients with respiratory diseases such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD). P. aeruginosa has been shown to reduce mucociliary clearance in airway epithelial cells by altering the trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Our collaborators determined that this detrimental effect is caused by a specific virulence factor known as the CFTR inhibitory factor (Cif). Cif is an epoxide hydrolase (EH) secreted from P. aeruginosa that negatively affects ABC transporters such as CFTR, TAP1, and P-Glycoprotein by altering their intracellular trafficking. We know that P. aeruginosa causes a reduction in apical CFTR levels by inhibiting USP10-mediated deubiquitination of CFTR and thus increases lysosomal destruction. This is the first report of an EH serving as a bacterial virulence factor, so while one downstream effect (CFTR degradation) is understood, the connection between Cif epoxide hydrolysis and dysregulated protein trafficking is unknown.