Coxiella burnetii is an obligate intracellular pathogen that grows within a specialized vacuole that is derived from fusion with lysosomes. Coxiella proteins that participate in the creation of this unique compartment and that modulate host cell functions are unknown. It has been proposed that a Cox/e//a-encoded type IVB protein secretion system is involved in host pathogenesis. The Coxiella type IVB system is functionally related to the Dot/lcm system found in the intracellular pathogen Legionella pneumophila. The similarity between these two bacterial type IV secretion systems has been exploited to identify Coxiella proteins that are translocated into eukaryotic host cells by the Legionella Dot/lcm system. The Coxiella proteins identified as substrates of the Dot/lcm system all contain multiple ankyrin-repeat domains, which are protein-protein interaction domains found in many eukaryotic proteins. The hypothesis to be tested is that these Coxiella Ank proteins are Dot/lcm substrates translocated into host cells during Coxiella infection and that these Ank proteins are directly involved in modulation of host cell functions. Examining the localization Ank proteins in cells infected with Coxiella will test whether these proteins are translocated. Ectopic production of Ank proteins in eukaryotic host cells will reveal host processes that are affected by Ank proteins. Cellular targets for the Ank proteins will be determined and additional substrates of the Coxiella Dot/lcm system will be identified using genetic and molecular approaches. These studies will elucidate pathogenic determinants that allow host cell infection by Coxiella and reveal intracellular infection strategies employed by this important pathogen.
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