Intracellular pathogens remain a leading cause of morbidity and mortality worldwide. The bacterial facultative intracellular pathogen Listeria monocytogenes is a cause of significant disease in certain predisposed hosts, such as pregnant women, neonates and the immunocompromised, and has a mortality of approximately 30%. Portnoy et. al. have developed a model system for the study of the intracellular growth and cell to cell spread of L. monocytogenes. Using this model, mutants defective in intracellular growth and cell to cell spread have been isolated and the importance of a hemolysin, listeriolysin O, as a virulence factor has been established. Listeriolysin O appears to be important in lysing the host phagolysosome, thus releasing the bacteria into the cytoplasm. In unpublished work, it has been shown that L monocytogenes has two distinct phospholipase C (PLC) activities. Mutants deficient in phosphatidylinositol specific phospholipase C activity are less virulent and have a three log higher LD50 in mice than wildtype. Although the exact role of this phospholipase is not established, mutants deficient in this activity have been shown to be defective in cell to cell spread. Consistent with this, they appear to have a decrease in the association with actin filaments typically seen with wildtype bacteria under electron microscopy, and which appear to be important in propelling the bacteria into adjacent cells. The role of PLC activity in signal transduction and release of membrane anchored proteins is well established in eukaryotes, however, although known for decades to exist in prokaryotes, their role here has not been well understood. This appears to be the first evidence for a specific role for PLC activity in prokaryotes. It is, thus, the purpose of this proposal to delineate the effects of PLC activity at the molecular and cellular level in L. monocytogenes, and ultimately to determine its importance as a virulence factor.
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