Characterizing the impact of small regulatory RNAs on the virulence of Brucella spp.

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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. Over the last few years, our laboratory has characterized genetic pathways that are critical for the intracellular survival and pathogenesis of Brucella strains, and specifically, we have identified small regulatory RNAs (sRNAs) that are essential for Brucella virulence. Preliminary experiments have revealed the presence of more than 20 novel sRNAs in B. abortus, and we have identified one of these sRNAs, called Bsr18 (for Brucella small RNA) that is required for the for virulence of B. abortus in a mouse model of chronic Brucella infection. We hypothesize that Bsr18 is produced under biologically relevant conditions, such as acidic pH, oxidative stress, nutrient limitation, and/or diminished oxygen, and moreover, we hypothesize that Bsr18 is required for the ability of B. abortus to cope with these conditions. Additionally, it is hypothesized that Bsr18 regulates the expression of genes important for the infectivity of B. abortus. Therefore, we plan to characterize the biological and regulatory functions of Bsr18, and in the end, the information gleaned from these studies may be used to develop new therapeutic and vaccine strategies against human Brucella infection.