The research in this proposal is aimed at understanding the genetic and molecular basis for the ability of the facultative intracellular pathogen, Legionella pneumophila to multiply within and kill human macrophages. Wild-type Legionella survive in macrophages by preventing phagosome-lysosome fusion. During the past period of this project, 20 genes were identified that are required for the ability of Legionella to multiply within and kill human macrophages and other host cells such as unicellular amoebae. Several genes were shown to be required for inhibition of phagosome- lysosome fusion at early times following infection. Based on database searches that showed homology to plasmid transfer proteins, it was found that Legionella was able to conjugate plasmid DNA and that several of these intracellular multiplication (Icm) Proteins are required for conjugation. This suggests that some of the Icm proteins may form a transfer apparatus. The gene products will be characterized genetically and biochemically. The hypothesis that some of the Icm products form a multisubunit complex will be tested. The relationship between DNA conjugation and intracellular multiplication will be studied and it will be determined if DNA transfer is an obligatory step in infection. The Icm proteins which function as effectors and interact with host cell components will be determined. Host cell components which interact with the Icm effectors will be identified.
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