“I chose Wake Forest University for two major reasons. The first is that, coming from a small, liberal arts college, I felt that I should enter a department that was small and very interconnected, which this department is. The second is that I wanted to be in a program that didn’t see graduate students as either a bother to train or as cheap labor; and the faculty in this department make it a priority to see that students are being well-trained and educated and that they are becoming the best possible scientists.”

Molecular basis for the targeting of mucA mutagenesis in Pseudomonas aeruginosa

Chronic Pseudomonas aeruginosa lung infections are the leading cause of death in cystic fibrosis (CF) patients. P. aeruginosa isolates from the environment or non-CF patients generally do not express the genes for alginate production, while the vast majority of CF isolates do produce the protective exopolysaccharide alginate, yielding a mucoid colony phenotype. Additionaly, a high percentage of CF P. aeruginosa isolates display a hypermutable phenotype, meaning that there is a higher mutation rate across the genome. Alginate production is controlled by the anti-sigma factor MucA. MucA acts by inactivating the sigma factor AlgT; with AlgT inactivated, the alginate genes will not be expressed resulting in a non-mucoid phenotype. The vast majority of mucoid P. aeruginosa CF isolates , harbor a mutation in mucA that causes a frameshift and a non-functional protein. This results in an active AlgT, which leads to alginate production, and a mucoid phenotype. However, the molecular basis for the targeting of mucA mutagenesis is unknown; understanding this is the major endeavor of my laboratory work. In E. coli the damage-inducible protein, dinP, is induced in situations of DNA damage; this dinP protein is an error-prone DNA polymerase that targets specific sequences for mutagenesis. This target sequence resembles the site of mucA that undergoes mutation during chronic lung infections in CF. A dinP orthologue exists in P. aeruginosa and we hypothesize that this dinP orthologue may be responsible for the targeted mutagenesis seen in mucA, resulting in the mucoid phenotype. Understanding the mechanism of mucoid conversion could lead to new methods of treatment for infection in CF patients.