Introduction. A variety of pathogenic microorganisms, including the Class B select agent Burkholderia pseudomallei, have devised strategies to withstand the challenges of the intracellular environment of professional phagocytes. Recent information has reveled that Burkholderia expresses a type III secretion system encoded in the bsa gene cluster that is essential to the intracellular survival of this pathogenic bacteria. The antimicrobial host defenses antagonized by the Burkholderia bsa type III secretion system are currently unknown. Oxygen-dependent antimicrobial systems are among the best characterized antimicrobial defenses of phagocytic cells. Our knowledge of the bidirectional relations between Burkholderia virulence factors and the host oxygen-dependent antimicrobial arsenal is fragmentary at best and in many instances conflictive. 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 of Burkholderia. Specifically, we propose to: 1) determine the contribution of the NADPH oxidase and iNOS to the art -Burkholderia activity of macrophages; 2) study the relation between the Burkholderia bsa type III secretion system and NADPH oxidase- or iNOS-mediated macrophage antimicrobial activity; and 3) characterize the Burkholderia bsa regulon expressed within macrophages. The knowledge gained in this application will increase our understanding of Burkholderia pathogenesis and will identify new potential targets 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 will intersect with numerous investigators and core facilities in our consortium. A detailed account of the interactions of this project with other members of project II.C [Drs. Vasil (project II.C.1), Voskuil (Project II.C.2) and Holmes (Project II.C.4)] has been described in the introduction of Project II.C and in the section titled """"""""Research Plan"""""""" of this application. In addition, we will interact with Dr. Robison (BYU Select Agent Archive) and Dr. Schweizer (Microbial Genetics, CSU) in aspects regarding the genetics and molecular biology of Burkholderia. Microarrays developed by Dr. Slayden will be obtained from our Genomics and Prntonmics Core. The potential prophylactic and therapeutic inteprention of bacterial and host target.
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