The Laboratory of James Kirby: Research
The long-term goal of my laboratory is to understand the interactions between pathogens and host that lead to vascular disease. Currently, we have been investigating the effects of two bacterial pathogens: Bartonella henselae and Bacillus anthracis.
Bartonella henselae causes cat scratch disease, a prolonged febrile illness associated with lymph node swelling. In AIDS patients, it causes a potentially life threatening angioproliferative disease known as bacillary angiomatosis. Considered an emerging infectious pathogen, Bartonella henselae has an number of unusual properties that make it especially worthy of study. First, it induces angiogenesis or new blood vessel formation. Therefore, study of this organism will likely contribute to our understanding of new blood vessel formation during pathological states such as cancer, wound healing, and diabetes. Second, Bartonella invades and replicates inside cells that line blood vessels, i.e., endothelial cells. In doing so, it causes sustained infection of the blood stream for months and may superinfect heart valves resulting in endocarditis.
Based on the potential insights that may be gained from this organism, my specific goals are to determine how Bartonella induces angiogenesis, to determine how Bartonella infects endothelial cells, and finally to determine the contributions of endothelial infection and angiogenesis towards successful infection of the host.
Using a cultured endothelial cell model, my laboratory showed that Bartonella induces endothelial proliferation in two different ways (Kirby and Nekorchuk, PNAS 2002). First, Bartonella stimulates mitosis. Second, it potently inhibits endothelial apoptosis. Since then, we have identified multiple signaling pathways responsible for Bartonella’s effects. We have also established the first in vitro model for Bartonella-induced angiogenesis (Kirby, Infection and Immunity, 2004; reviewed in ASM News, 2005, 71(1), 11-12) and are using it to study host-pathogen interactions in this more complex environment.
Bacillus anthracis causes an almost universally fatal illness in its systemic form. The cardinal terminal pathologies of anthrax are hemorrhage, edema, and thrombosis, i.e., vascular pathologies. However, the pathophysiological basis for these events are not understood. Since modern antibiotics and supportive therapy are largely ineffective, our long-term goal is to determine the basis of vascular damage at a structural and molecular level, as a guide in developing new therapies targeting vascular damage. As part of this exploration, we determined that anthrax lethal toxin induces apoptosis of endothelial cells in in vitro models (Kirby, Infection and Immunity, 2004). To allow us to investigate the nature of anthrax-induced vascular damage, we have established a simple and safe murine model using an anthrax strain that does not infect humans (Duong, Chiaraviglio, and Kirby, 2006). Through detailed histopathological analysis we determined that this model recapitulates major human pathologies including hemorrhage, edema, pneumonia, and lymphocytolysis. Using this model, we are analyzing effects of anthrax toxins and the underlying basis of vascular damage.
Additional projects include collaborations to apply novel technologies to clinical microbiology diagnostics.
Positions
Opening for postdoctoral fellow or advanced research assistant to help with the development of novel (non antibiotic resistance marker based) selectable and counterselectable markers systems for Bacillus anthracis research. Excellent molecular biology skills required.
Selected Recent Publications
Duong, S, Chiaraviglio, L, and Kirby, JE. Histopathology in a Murine Model of Anthrax. International Journal of Experimental Pathology. 2006; 87, 131-137
Kirby JE. Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis. Infection and Immunity. 2004; 72(1), 430-439.
Kirby, JE. An In Vitro Model of Bartonella henselae Induced Angiogenesis. Infection and Immunity. 2004; 72(12),7315-7.
Kirby, JE and Nekorchuk DM. Bartonella-associated endothelial proliferation depends on inhibition of apoptosis. Proc Natl Acad Sci USA. 2002; 99(7):4656-61
