Characterizing a novel Brucella small RNA critical for cell envelope integrity

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 Bsr7 (for Brucella small RNA) that is required for the ability of the
bacteria to withstand outer membrane stress. Given the strong connection between Bsr7 and the integrity of
the cellular envelope, we hypothesize that deletion of Bsr7 will lead to significant attenuation of B. abortus in
both macrophage and animal models of infection. Additionally, we hypothesize that Bsr7 is produced under
biologically relevant conditions, such as acidic pH, oxidative stress, nutrient limitation, and/or diminished
oxygen. Moreover, it is hypothesized that Bsr7 regulates the expression of genes important for the infectivity of
B. abortus. Therefore, we plan to characterize the biological and regulatory functions of Bsr7, and in the end,
the information gleaned from these studies may be used to develop new therapeutic and vaccine strategies
against human Brucella infection.

Grant Number: 5R21AI183022-02
NIH Institute/Center: NIH
Principal Investigator: Clayton Caswell