Activity of Pseudomonas Type III Toxins

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DESCRIPTION (provided by applicant): Understanding the dynamic interaction between host and parasite offers opportunities to prevent damage to host tissues and limit parasitic replication. The Pseudomonas type III system plays an important role in acute infections and may play an initial role in the establishment of chronic infections. Four effectors or toxins, ExoS, ExoT, ExoY and ExoU, are directly injected into eukaryotic cells by the secretion apparatus and all share important properties. Each effector is an enzyme and each enzyme requires a eukaryotic cofactor or activator for maximal activity. Catalytic activity ensures rapid intoxication and alteration of cellular physiology to benefit bacterial replication and survival in a host environment. Inactivation of key elements of cellular defenses that include cytoskeletal components important for phagocytosis and bacterial destruction (ExoS, ExoT, ExoY), intercellular interactions (ExoY), cell signaling pathways (ExoS, ExoT, ExoY) and membrane integrity (ExoU) alter the innate immune responses and can aid not only in establishing the infection but also allow expression of other virulence factors to promote dissemination to other tissues. The current application builds upon our discovery of the mechanism of action of ExoU (phospholipase) and recent data implicating superoxide dismutase (SOD) as a cofactor for ExoU. Importantly, mammalian SODs are localized to both intracellular and extracellular compartments. We postulate that the localization of the cofactor for ExoU- phospholipase activity may govern the biologic activities of the enzyme and promote either colonization or dissemination at certain stages of bacterial invasion. Understanding how the elements critical to enzymatic activity work together to alter the protein will allow rational development of inhibitors that interrupt the pathological consequences of serious P. aeruginosa infections. Importantly, these studies could reveal evolutionary insights regarding the relationships between the cofactors, bacterial enzymes and their mammalian homologs (JPLA2, cPLA2 and patatin). Finally lipid metabolism and the production of arachidonic acids effect immune function and the regulation of cellular metabolism. Investigating the biological consequences of ExoU intoxication may lead to new insights regarding the inflammatory response to P. aeruginosa and its products and may result in the design of a combination of therapeutics that could aid individuals who are critically ill or in the early stages of chronic infection.