Introduction The goal of this project is to identify the major molecular components of the adaptive responseof Burkholderia pseudomalleiio reactive oxygen and nitrogen stress. B. pseudomallei is the causative agentof melioidosis. High mortality rates, difficult treatment regimens, and the wide availability of pathogenicstrains have led to the classification of B. pseudomallei as a potential bioterrorism agent. More effectivetreatments and an efficacious vaccine are needed to defend against a B. pseudomallei attack. During thecourse of infection, intracellular pathogens must cope with a variety of host-mediated stress conditions, inparticular, the antibacterial properties of phagocytic cells. B. pseudomallei invades and persists inmacrophages. Macrophages produce antimicrobial reactive oxygen and nitrogen species (ROS and RNS).Mechanisms by which intracellular pathogens avoid these antibacterial agents are central to their survivalduring infection. Genes involved in resistance to ROS that are present in the B. pseudomallei genomeinclude the oxyR and soxR genes, and the genes for superoxide dismutases, catalases, and alkylhydroperoxide reductases. Our working hypotheses are: 1) mechanisms which allow B. pseudomallei toresist killing by ROS and RNS are critical for survival during disease and are thus logical candidates forantimicrobial intervention and 2) resistance proteins are highly expressed during disease and thus idealcandidates for vaccine development. We will study B. pseudomallei's adaptation to oxidative and nitrosativestress using global expression profiling methods refined in our studies of Mycobacterium tuberculosis. Wewill identify the transcriptional response of B. pseudomallei to ROS and RNS, determine the role of the majoroxidative stress regulators (OxyR and SoxR) in defense against ROS and RNS, and identify key resistanceproteins for vaccine and drug development. Project interactions In addition to the interactions described inthis proposal with other project members (e.g. Drs. Vasil, Holmes, & Vazquez-Torres), we will interact withDr. Slayden (Genomics/Proteomics Core-CSU) in the development and use of microarray technology andthe evaluation of potential target proteins for therapeutic agents, Dr. Robinson (Select Agent Archive-BYU)for access to representative B. pseudomallei isolates, and Dr. Schweizer (Microbial Genetics-CSU) in termsof genetics of B. pseudomallei.
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