Elucidating the regulatory mechanism of a Brucella-specific small RNA required for virulence

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 determined that one sRNA, called MavR, for MurF- and virulence-regulating
sRNA is required for full virulence of B. abortus in a mouse model of chronic Brucella infection. Preliminary
work has demonstrated that MavR is a negative regulator of MurF, which is an essential enzyme involved in
peptidoglycan biosynthesis. Taken together, these data led us to develop a model for the MavR-MurF genetic
pathway that is critical for Brucella virulence, and the work outlined in this application will test several
independent hypotheses associated with this important genetic circuit. 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: 5R21AI182899-02
NIH Institute/Center: NIH
Principal Investigator: Clayton Caswell