THE ROLE OF GAMMA-AMINOBUTYRIC ACID (GABA) IN THE PATHOGENESIS OF BRUCELLA

Project Summary Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading toabortions and sterility, and these bacteria are also capable of causing debilitating human infections, whichoften result from human exposure to infected animals and animal products. Brucella spp. are consideredthreats as potential biological weapons. Importantly, antibiotic treatment against brucellosis is prone to diseaserelapse, and there is currently no safe and effective vaccine to protect humans against infection with Brucella.The brucellae are intracellular pathogens that reside within immune cells called macrophages where theyreplicate in a specialized compartment, and the capacity of Brucella to survive and replicate withinmacrophages is essential to their ability to cause disease. Over the last few years, our laboratory hascharacterized a genetic pathway that is critical for the intracellular survival and pathogenesis of Brucella strains,and recently, we have discovered that one arm of this genetic circuitry controls the production of an ABCtransport system, called GasABCDE, that is essential for Brucella virulence. Preliminary experiments revealed that GasE is required for the ability of Brucella abortus to colonizeexperimentally infected mice. Moreover, bioinformatic analyses determined that GasABCDE is homologous toABC transporters in other closely related bacteria that function in the import of ?-aminobutyric acid (GABA),and experiments in our lab have demonstrated that GasABCDE is a bona fide GABA transporter in B. abortus.We have also demonstrated that GABA uptake by the brucellae results in transcriptional changes, leading tothe hypothesis that Brucella strains use GABA as a means of sensing the intracellular environment of the hostmacrophage. Overall, very little is known about the role of GABA in bacterial pathogenesis, and the currentproject is designed to define how GABA and the transport of GABA are linked Brucella virulence. In the end, itmay be possible to target bacterial GABA transport systems with novel vaccines and/or therapeutic strategies.