Yian Kim Tan PhD Biodefense Candidate Date: Thursday January 22, 2008 Time: 9:00 a.m. Place: George Mason University, Prince William campus Discovery Hall Auditorium Dissertation Director: Dr. Aiguo Wu, M.D., Defense Threat Reduction Agency Dissertation Chair: Dr. Charles Bailey, Ph.D., National Center for Biodefense and Infectious Diseases Title: Novel Functions of Anthrax Lethal Toxin
Autophagy is an evolutionary conserved intracellular process whereby cells break down long-lived proteins and organelles. Accumulating evidences suggest increasing physiological significance of autophagy in pathogenesis of infectious diseases. In addition to the myriad of effects that LT exerts on different cell types, we describe herein a novel effect of LT-induced autophagy on mammalian cells. Several autophagy biochemical markers including LC3-II conversion, increased punctuate distribution of GFP-LC3 and development of acidic vesicular organelles (AVO) were detected in cells treated with LT. Analysis of individual LT component revealed a moderate increase in LC3-II conversion for protective antigen-treated cells, whereas the LC3-II level in lethal factor-treated cells remained unchanged. Moreover, our preliminary findings suggest a protective role of autophagy in LT intoxication as indicated by accelerated cell death when autophagy was inhibited. Separately, LT was also shown to induce harmful levels of reactive oxygen species (ROS) in immune cells although antioxidant appeared to have some protective effects against its damaging effects. In addition, chemotaxis analysis revealed that LT not only fail to elicit chemokines production in immune cells but also suppressed the chemokines-inducing properties of lipopolysaccharides (LPS) and bacterial cell wall (CW). The wide array of effects that LT exerts on various immune cells reflects the intricacies of the intoxication mechanisms. These findings enhance our understanding of anthrax pathogenesis and may prove to be relevant to the development of a more effective countermeasure against anthrax.
A copy of the dissertation is on reserve in the Johnson Center Library, Fairfax campus. The doctoral project will not be read at the meeting, but should be read in advance.
All members of the George Mason University community are invited to attend.