Characterization of the Brucella abortus virB Locus

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DESCRIPTION (provided by applicant): 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 persist in the host are unknown. We have recently shown that the virB genes, encoding a Type IV secretion system (T4SS), are essential for persistence of B. abortus in mice. Our long-range goal is to elucidate the molecular mechanism by which the T4SS mediates persistent infection by B. abortus. The objective of this application is to characterize the role of the T4SS in evading host immunity. The central hypothesis of this application is that the T4SS mediates persistent colonization by allowing B. abortus to evade a specific component of adaptive immunity. This hypothesis has been formulated on the basis of our preliminary data showing that (i) virB mutants are able to colonize the mouse, but are eliminated with the onset of adaptive immunity, and (ii) mutant mice that are unable to generate CD4+ T cell and B cell dependent adaptive immunity, are defective in clearing a virB mutant. We are uniquely prepared to undertake the proposed research, because we have identified a virulence factor (T4SS) required for immune evasion and have experience in working with in vitro and in vivo models of brucellosis. The central hypothesis will be tested and the objectives of this application accomplished by pursuing two specific aims: (1) Identify the mechanism by which the T4SS mediates evasion of CD4+ T cell- and/or B cell-dependent immune responses (2) Determine whether the T4SS enables; Brucella to evade antigen presentation via MHC class II. This research is innovative since it employs both mouse and bacterial genetics to identify how a specific virulence factor functions in evasion of host immunity. We expect that the results of this work will identify specific immune mechanisms evaded by B abortus using the T4SS. These results will be significant, because knowing which specific immune mechanisms are evaded by Brucella will facilitate the development of new strategies to treat or prevent brucellosis.