Introduction. A variety of pathogenic microorganisms, including the Class B select agent Burkholderiapseudomallei, have devised strategies to withstand the challenges of the intracellular environment ofprofessional phagocytes. Recent information has reveled that Burkholderia expresses a type III secretionsystem encoded in the bsa gene cluster that is essential to the intracellular survival of this pathogenicbacteria. The antimicrobial host defenses antagonized by the Burkholderia bsa type III secretion system arecurrently unknown. Oxygen-dependent antimicrobial systems are among the best characterized antimicrobialdefenses of phagocytic cells. Our knowledge of the bidirectional relations between Burkholderia virulencefactors and the host oxygen-dependent antimicrobial arsenal is fragmentary at best and in many instancesconflictive. The overall goal of this application is to analyze the importance of oxygen-dependent (i.e.,reactive oxygen and nitrogen species) antimicrobial defenses of macrophages in the pathogenesis ofBurkholderia. Specifically, we propose to: 1) determine the contribution of the NADPH oxidase and iNOS tothe art-Burkholderia activity of macrophages; 2) study the relation between the Burkholderia bsa type IIIsecretion system and NADPH oxidase- or iNOS-mediated macrophage antimicrobial activity; and 3)characterize the Burkholderia bsa regulon expressed within macrophages. The knowledge gained in thisapplication will increase our understanding of Burkholderia pathogenesis and will identify new potentialtargets for prophylactic and therapeutic intervention against this fastidious intracellular pathogen.Project interactions. Dr. Vazquez-Torres is the PI of project II.C.3. Research proposed in this project willintersect with numerous investigators and core facilities in our consortium. A detailed account of theinteractions of this project with other members of project II.C [Drs. Vasil (project II.C.1), Voskuil (ProjectII.C.2) and Holmes (Project II.C.4)] has been described in the introduction of Project II.C and in the sectiontitled 'Research Plan' of this application. In addition, we will interact with Dr. Robison (BYU Select AgentArchive) and Dr. Schweizer (Microbial Genetics, CSU) in aspects regarding the genetics and molecularbiology of Burkholderia. Microarrays developed by Dr. Slayden will be obtained from our Genomics andPrntonmics Core. The potential prophylactic and therapeutic inteprention of bacterial and host target.
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