The research program in the Frank lab centers on the pathogenesis of two Gram-negative bacteria, Pseudomonas aeruginosa and Francisella tularensis. P. aeruginosa is a bacterium that is an inhabitant of soil and water. Normal individuals are generally not susceptible to P. aeruginosa-mediated infections, however, several underlying conditions or traumas increase the risk for an acute episode. These conditions include extensive burns, eye trauma, mechanical ventilation, HIV infection, neutropenia or malignancy. Cystic fibrosis (CF) patients often suffer from life-long chronic colonization by P. aeruginosa. The constant presence of bacterial antigens coupled with intense inflammatory responses contributes to diminution of lung function and quality of life. Regardless of the type of infection, antimicrobial treatment is complicated by a notable intrinsic resistance and emergence of multi-drug resistant strains. Dr. Frank's lab was instrumental in the initial discovery and characterization of the P. aeruginosa type III system. Her laboratory continues the study of this system and the toxins that are injected into eukaryotic cells. Major research goals of the program include the development of specific enzyme inhibitors, antibody reagents or vaccines that neutralize the tissue-damaging toxins that P. aeruginosa synthesize. She has a single chain antibody therapeutic currently in clinical trials and is continuing to study the mechanistic features and biological outcomes of type III-mediated delivery of toxins. Francisella tularensis is the etiologic agent that causes tularemia in humans and animals. The organism poses a serious threat as only a few bacteria (10-50 colony forming units) are necessary to avoid innate immunity and rapidly replicate in the lymphoid tissues of human hosts. As part of the national biodefense program, the Frank lab in collaboration with Dr. Thomas C. Zahrt developed research strategies to understand the pathogenesis of F. tularensis using genetic approaches. The goals of this project are to identify virulence factors as potential targets for therapeutic or vaccine development and to understand how these factors work in concert to overcome the host innate defenses.