Brucella abortus is a facultative intracellular pathogen that is highly infectious by the aerosol route and causes a chronic, debilitating disease. The molecular mechanisms employed by this pathogen to cause disease are largely unknown. We have recently shown that a Type IV secretion system (T4SS), encoded by the virB locus, is essential for virulence and persistence of B. abortus in mice. Our long-range goal is to elucidate the molecular mechanism by which the T4SS mediates intracellular survival of B. abortus and persistent infection. The objective of this application is to identify effectors that are translocated by the T4SS into host cells. The central hypothesis of this application is that the B. abortus T4SS secretes effector proteins into the host cell that mediate intracellular survival. This hypothesis has been formulated on the basis of our preliminary data which (i) demonstrated the essential role of the T4SS in virulence and bacterial persistence in both the mouse model and in cultured macrophages and (ii) identified candidate effector proteins of the T4SS, including the secreted protein BspA, using a bioinformatic Brucella suis genome screen. The rationale for the proposed research is that characterization of B. abortus virulence factors mediating specific interactions with host cells will form the basis for new approaches to treat or prevent brucellosis. The objectives of this application accomplished by pursuing the following specific aim: Determine whether candidate Type IV effectors identified by bioinformatic comparison between the genomes of B. suis and the closely related extracellular plant pathogen Agrobacterium tumefaciens are secreted by B. abortus and/or translocated into host cells via the T4SS. This research is innovative since it employs a novel genomic in silico screen for identifying effector candidates. It is our expectation that the results of this work will identify B. abortus Type IV effector proteins that will form the basis for a future R01 application to characterize their function.
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