Brucella spp. are bacteria that naturally infect a variety of domesticated and wild animals leading to abortions and sterility, and these bacteria are also capable of causing debilitating human infections, which often result from human exposure to infected animals and animal products. Brucella spp. are considered threats as potential biological weapons. Importantly, antibiotic treatment against brucellosis is prone to disease relapse, 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 they replicate in a specialized compartment, and the capacity of Brucella to survive and replicate within macrophages is essential to their ability to cause disease. Over the last few years, our laboratory has characterized 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 ABC transport system, called GasABCDE, that is essential for Brucella virulence. Preliminary experiments revealed that GasE is required for the ability of Brucella abortus to colonize experimentally infected mice. Moreover, bioinformatic analyses determined that GasABCDE is homologous to ABC 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 to the hypothesis that Brucella strains use GABA as a means of sensing the intracellular environment of the host macrophage. Overall, very little is known about the role of GABA in bacterial pathogenesis, and the current project is designed to define how GABA and the transport of GABA are linked Brucella virulence. In the end, it may be possible to target bacterial GABA transport systems with novel vaccines and/or therapeutic strategies.

Public Health Relevance

Brucella spp. are bacteria that cause a debilitating, flu-like disease in humans, and these bacteria are classified as Select Agents due to their potential use as biological weapons. Currently, no safe and effective vaccine exists to protect against human Brucella infection. The proposed research will define a novel transport system in Brucella biology that may be targeted for vaccine and/or therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI125958-01A1
Application #
9601292
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
2018-06-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061