(3x) Studying Host-Pathogen Interactions In Model Membrane Systems: Lessons Learned From a Bacterial Toxin

During my Ph.D. work at Drexel University, I worked in the Biological Colloids Laboratory, where I applied a colloidal science/engineering approach to the study of a biochemical problem, that of characterizing lipid rafts.  (These cholesterol-rich regions of the cell membrane are proposed to be involved in cellular processes, such as signal transduction and protein trafficking.)  This work not only introduced me to the fascinating world of lipids and membrane biophysics but also revealed a division that exists between researchers studying the same problem with different approaches: biologists employing “real” biological systems (live cells) and engineers/colloid scientists studying “model” (liposome) systems.  This division was particularly acute in the lipid raft field, where there remains a lack of consensus about the size of lipid rafts, 18 years after their first discovery.  I feel strongly that each side of this debate has its merits and flaws and that to truly solve this problem, the two fields, biology and engineering, must work together.  My research goal is to bridge the gap between the biological and engineering worlds, employing engineering philosophies, techniques, and tools to solve biological problems. 

To gain the skills necessary to achieve this goal, I pursued a postdoctoral research project at the University of Pennsylvania, School of Dental Medicine.  In this project, I have applied my background in lipid phase behavior to study the mechanism of action of a bacterial protein toxin, the leukotoxin (LtxA) produced by Aggregatibacter actinomycetemcomitans.  LtxA kills human white blood cells in a manner that has long been assumed to involve pore formation.  However, by focusing on the lipid-specific interactions of the toxin, we were able to determine that the cytolytic mechanism is more complex than simple pore formation and instead involves several types of lipid phase changes. Using the expertise of the laboratory, we then related these model results to our results obtained in human immune cells.

In this poster, I will describe our two-part approach (using both model systems and natural cells) and demonstrate what it has allowed us to determine about the mechanism of action of LtxA to illustrate the power of this approach to study host-pathogen interactions.  I will also describe my future plans to use these techniques to study the interesting behavior of LtxA and other toxins and extend this work to future studies involving other types of pathogens, such as the herpes simplex virus type 1 (HSV-1).  I am particularly interested in applying this method to study mechanisms by which pathogens “hijack” elements of the host defense system (particularly the cell membrane) for their own purposes.

This cross-disciplinary nature of this approach to study disease pathology has been met with great interest in the oral microbiology and immunology field, resulting in an F32 postdoctoral fellowship from the NIH NIDCR and a number of colleagues expressing interest in pursuing collaborations.  The types of studies I intend to pursue in a future faculty position will allow me to take advantage of some of the new funding opportunities that have been created recently as both governmental funding agencies and private foundations have recognized the importance of these types of cross-disciplinary studies.