O2-Dependent Host Defenses in Resistance to Burkholdria

导论.多种病原微生物，包括B类选择性病原体伯克霍尔德氏菌 已经设计出策略来抵抗细胞内环境的挑战， 专职吞噬细胞最近的信息揭示，伯克霍尔德菌表达III型分泌物 系统编码的bsa基因簇是必不可少的细胞内生存的这种致病 细菌由Burkholderia bsa III型分泌系统拮抗的抗微生物宿主防御是 目前未知。氧依赖性抗菌系统是最具特征的抗菌系统之一， 吞噬细胞的防御。我们对伯克霍尔德氏菌毒力之间双向关系的认识 在许多情况下， 矛盾本申请的总体目标是分析氧依赖性（即， 活性氧和氮类）的抗菌防御巨噬细胞的发病机制， 伯克霍尔德氏菌具体而言，我们建议：1）确定NADPH氧化酶和iNOS对 巨噬细胞的抗伯克霍尔德菌活性; 2）研究Ⅲ型伯克霍尔德菌 分泌系统和NADPH氧化酶或iNOS介导的巨噬细胞抗微生物活性;和3） 表征巨噬细胞内表达的伯克霍尔德氏菌bsa调节子。在此过程中获得的知识 应用将增加我们对伯克霍尔德氏菌发病机制的理解，并将发现新的潜力， 针对这种挑剔的细胞内病原体的预防性和治疗性干预的目标。 项目互动。Vazquez-Torres博士是II.C.3项目的主要研究者。本项目提出的研究将 与我们联盟中的众多调查员和核心设施有交集。详细介绍了 本项目与项目二. C其他成员的互动[Vasil博士（项目二. C. 1）、Voskuil博士（项目二. C. 1）、 项目二. C的导言和项目二. C一节中介绍了项目二. C（项目二. C. 2）和霍姆斯（项目二. C. 4）]的情况。 “研究计划”是这个应用程序的一部分。此外，我们还将与Robison博士（杨百翰大学精选代理人）进行互动 档案）和Schweizer博士（微生物遗传学，CSU）在遗传学和分子生物学方面的研究。 伯克霍尔德氏菌的生物学Slayden博士开发的微阵列将从我们的Genomics获得， Prntongling 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.