Interdisciplinary Training

Penelope Barnes

"Role of Cystic Fibrosis Transmembrane Regulator in A. fumigatus Epithelial Cell Interactions"

Chronic pulmonary microbial infection and resultant destructive inflammatory process is still the major cause of morbidity and mortality in cystic fibrosis (CF) patients. One contributor to this process is Aspergillus fumigatus, a ubiquitous mold. In the normal host, inhalation of A. fumigatus into airways results in asymptomatic clearance by mechanisms requiring macrophages and Th1 lymphocytes. However, in CF patients, the Th1 response is shifted to Th2, resulting in failure to clear the organisms and a destructive inflammatory response. The reason that CF patients develop a bias toward Th2 in response to A. fumigatus infection is unknown.

The defect in CF patients includes a variety of mutations in the gene encoding a chloride channel, the CFTR, which is located on epithelial cells and macrophages. A. fumigatus conidia bind and enter lung epithelial cells . However, the identity of the A. fumigatus ligands on epithelial cells and the subsequent inflammatory response after internalization have not been reported. This Fellowship will examine the interaction of A. fumigatus with lung epithelial cells. We hypothesize that the epithelial cell- A. fumigatus interactions play a role in directing the bias towards either a Th1 or a Th2 lymphocyte response to A. fumigatus, with the CFTR protein having a pivotal function in mediating inflammation. We will characterize binding and uptake of A. fumigatus into normal and CFTR deficient human and mouse lung epithelial cells and investigate the resultant cytokine production. We will then characterize the inflammatory response to A. fumigatus in wild-type and CFTR deficient mice.