Regulation of the Brucella abortus general stress response

Project Summary/Abstract The goal of this research proposal is to advance molecular-level understanding of a conserved signal transduction system that influences the ability of Brucella abortus to survive chemical and physical stress conditions, and to colonize mammalian hosts. The general stress response (GSR) signaling system controls stress adaptation and chronic infection in a mammalian model of brucellosis. We are working to understand how B. abortus detects environmental signals via a set of HWE-family histidine kinases to influence infection. We have preliminary evidence that two sensor kinases coordinately control GSR activation and infection in B. abortus. We have further discovered that previously uncharacterized genes regulated by the GSR system – eipB, gsrN1 and gsrN2 – are determinants of mammalian infection. These conserved genes protect Brucella spp. from cell envelope stress and control stress-dependent gene expression at the post-transcriptional level, respectively. Investigation of these genes will define the molecular underpinnings of infection in an understudied pathogen of significant human health and agricultural import. Given that sensor histidine kinases are not present in mammals, the basic biochemical and genetic experiments we propose here have the potential to inform new treatments for microbial infection targeted to sensory histidine kinases. Proposed studies will be conducted by investigators that have expertise working on this select agent under high containment BSL3 conditions. The specific aims of this project are: 1) Define the mechanism of stress signal detection by a multi-kinase sensory system 2) Characterize the mechanism by which EipB contributes to cell envelope function 3) Determine the mechanism by which the small RNAs GsrN1 and GsrN2 regulate Brucella infection biology