Pseudomonas aeruginosa is important in the treatment of cancer through the use of the Exotoxin A fused to a variety of different proteins so as to target cytotoxicity specifically to tumor cells. This has been accomplished by others through the use of chimeric Exotoxin A fusions with proteins such as granulocyte colony-stimulating factor (G-CSF), luteinizing hormone releasing hormone, transforming growth factor (TGF)-alpha, Interleukin-4, Interleukin-13, and others. In addition, acting as an infectious agent in its own right, Pseudomonas aeruginosa causes severe and often deadly infections in cancer patients. Treatment of infection by P. aeruginosa is often difficult due to the resistance of this pathogen to antibiotics.

Certain clinical isolates of P. aeruginosa are cytotoxic due to the production of the 74 kDa protein toxin ExoU. Previously, we have found that the bacterium uses the ExoU toxin to degrade the host cell phospholipids- greasy molecules that are an essential part of cell membranes. We also found that drugs known to block proteins that degrade phospholipids are able to protect cells from the deadly effect of the toxin. My current research involves understanding how ExoU becomes activated inside the host cell, an area which could potentially lead to new therapies in protecting cells from the ExoU toxin. Understanding the mechanism of this toxin may provide new modes of treatment for cancer patients infected with cytotoxic strains of P. aeruginosa. In summary, this work will provide greater insight into the mechanisms of cytotoxicity by P. aeruginosa, acting through multiple toxins, including Exo U and Exotoxin A. In addition, this work will expand our knowledge of the use of Pseudomonas toxins as a means of cytotoxic targeting of human tumor cells.

PUBLICATIONS (resulting from this training)

Birtalan SC, Phillips RM, Ghosh P. (2002) Three-dimensional secretion signals in chaperone-effector complexes of bacterial pathogens. Mol Cell. 9:971-80.

Phillips RM, Six DA, Dennis EA, Ghosh P. (2003) In vivo phospholipase activity of the Pseudomonas aeruginosa cytotoxin ExoU and protection of mammalian cells with phospholipase A2 inhibitors. J Biol Chem. 278:41326-32.