O2-Dependent Host Defenses in Resistance to Burkholdria

导言。各种致病微生物，包括B类选择剂伯克霍尔德氏菌 已经设计出策略来抵抗细胞内环境的挑战 专业吞噬细胞。最近的信息显示，伯克霍尔德氏菌表达一种III型分泌物 编码在BSA基因簇中的系统，对于这种病原体的细胞内生存是必不可少的 细菌。伯克霍尔德氏菌BSA III型分泌系统对抗的抗微生物宿主防御是 目前尚不清楚。氧依赖抗菌系统是最具特性的抗菌剂之一。 吞噬细胞的防御。我们对伯克霍尔德氏菌毒力双向关系的认识 因素和宿主氧依赖的抗菌药库充其量是支离破碎的，在许多情况下 自相矛盾。本申请的总体目标是分析氧依赖的重要性(即， 巨噬细胞的抗微生物防御在其发病机制中的作用 伯克霍尔德里亚。具体地说，我们建议：1)确定NADPH氧化酶和iNOS对 巨噬细胞的伯克霍尔德氏菌活性；2)研究伯克霍尔德氏菌与BSAⅢ型的关系 分泌系统和NADPH氧化酶或iNOS介导的巨噬细胞抗菌活性；3) 鉴定在巨噬细胞中表达的伯克霍尔德氏菌BSA调节子。从这一过程中获得的知识 应用将增加我们对伯克霍尔德氏菌发病机制的了解，并将发现新的潜力 针对这种挑剔的细胞内病原体的预防和治疗干预的目标。 项目交互。巴斯克斯-托雷斯博士是项目二.C.3的负责人。该项目中提出的研究将 与我们财团的众多调查人员和核心设施进行交叉调查。详细介绍了 本项目与项目二.C其他成员的互动情况[Vasil博士(项目二.C.1)，Voskuil(项目 第二.C.2)和Holmes(项目二.C.4)]已在项目二.C的导言和第#节中作了说明。 本申请书的标题为“研究计划”。此外，我们还将与Robison博士(杨百翰精选工程师 档案)和Schweizer博士(微生物遗传学，CSU)在遗传学和分子方面的研究 伯克霍尔德里亚的生物学。由斯莱登博士开发的微阵列将从我们的基因组学和 Prntonmics Core。细菌和宿主靶点的潜在预防和治疗干预。

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.