Monday, May 6, 2024
5/6/2024
Project Summary 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. Interestingly, quorum sensing is an important component of Brucella virulence, but traditionally, quorum sensing is an activity performed by large populations of bacteria, while the brucellae exists primarily in intracellular vacuoles in small numbers. Thus, the Brucella quorum sensing system is atypical to the paradigm of Gram-negative quorum sensing systems, and this application seeks to define novels elements of this pathway. Preliminary work in our group led to the development of a B. abortus strain that is unable to sense the quorum sensing molecule, acyl homoserine lactone (AHL). Deletion of the two genes encoding transcriptional regulators of the LuxR family yielded a quorum sensing “deaf” strain, and this strain will be used to define the Brucella quorum sensing transcriptome in order to identify genetic elements critical to virulence. Additionally, we will test the hypothesis that the quorum sensing “deaf” strain will be highly attenuated in both cellular and animal models of Brucella infection. Finally, it is known that Brucella strains produce a 12 carbon AHL, but no genes are present that encode known AHL synthases. As such, we have developed an unbiased screening strategy to identify the Brucella AHL synthase. In the end, the information gleaned from these studies may be used to develop new therapeutic and vaccine strategies against human Brucella infection.
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