Contact Dependent Growth Inhibition in Burkholderia pseudomallei

描述（由申请方提供）：类鼻疽伯克霍尔德菌是一种革兰氏阴性环境腐生性微生物，在东南亚和澳大利亚北方流行，可引起类鼻疽病，一种严重且通常致命的人类疾病。因为它比以前认识到的要普遍得多和/或传播超出了既定的边界，B。类鼻疽是一个严重的全球性传染病问题。它也是一种潜在的生物恐怖主义制剂，已被列为NIAID B类优先病原体。它所带来的威胁突出表现在其极低的感染剂量、通过气溶胶途径引发感染的能力、对常用抗生素的内在抗性、缺乏疫苗、缺乏快速诊断测试以及美国医生对该疾病的不熟悉。即时诊断的开发、潜在疫苗成分的鉴定和新疗法的开发仍然是高度优先的目标。接触依赖性生长抑制（CDI）是在大肠杆菌的特定菌株中发现的一种现象，其中细菌产生称为CdiA的大的表面定位蛋白质抑制大肠杆菌的生长。在细胞-细胞接触时不产生CDI系统的大肠杆菌。我们对B的初步研究。假鼻疽的研究表明，CDI系统广泛存在于革兰氏阴性细菌中，并且它们在杀死靶细胞的CdiA蛋白和保护抑制剂细胞的免疫蛋白区域中具有多态性。变异性在B中尤其明显。类鼻疽菌株。我们建议测试的假设，伯克霍尔德菌BtpAIB蛋白质的功能作为等位基因特异性细菌间CDI系统。我们将确定它们是否以物种内和/或物种间的方式发挥作用。我们还将确定BtpAI B蛋白是否有助于B。假鼻疽，如果是，如果CDI是需要这种能力。了解CDI系统在B中的功能。假鼻疽的研究将使我们更深入地了解这些复杂病原体致病策略的分子机制，所获得的信息可能使我们能够利用CDI系统开发治疗类鼻疽和消除B的新方法。污染环境中的假鼻疽 公共卫生相关性： 类鼻疽伯克霍尔德氏菌引起严重且通常致命的类鼻疽病，是一种新兴的传染病病原体和潜在的生物战剂，我们缺乏快速诊断、有效治疗和疫苗。我们将检验这个假设，即B。pseudomallei btpAIB基因编码多态性细菌间竞争系统，并且它们在毒力中起作用。这些系统的表征可以使它们被开发为用于治疗类鼻疽病和/或消除B的新型抗微生物剂。从受污染的环境中获得假鼻疽。

DESCRIPTION (provided by applicant): Burkholderia pseudomallei is a Gram-negative environmental saprotroph endemic to southeast Asia and northern Australia that causes melioidosis, a serious and often lethal human disease. Because it is far more prevalent than previously recognized and/or spreading beyond established boundaries, B. pseudomallei is a serious emerging global infectious disease problem. It is also a potential bioterrorism agent that has been classified as an NIAID Category B Priority Pathogen. The threat it presents is underscored by its extremely low infectious dose, its ability to initiate infection by an aerosol route, its intrinsic resistance to commonly used antibiotics, lack of a vaccine, lack of a rapid diagnostic test, and unfamiliarity of U.S. physicians with the disease. The development of point-of-care diagnostics, the identification of potential vaccine components, and the development of new therapeutics remain high priority goals. Contact Dependent Growth Inhibition (CDI) is a phenomenon discovered in a specific strain of Escherichia coli in which bacteria producing a large surface-localized protein called CdiA inhibit the growth of E. coli that do not produce CDI systems upon cell-cell contact. Our preliminary studies with B. pseudomallei revealed that CDI systems are widespread amongst Gram-negative bacteria and that they are polymorphic in the regions of the CdiA proteins that kill target cells and the immunity proteins that protect inhibitor cells. Variability is especially pronounced amongst B. pseudomallei strains. We propose to test the hypothesis that Burkholderia BtpAIB proteins function as allele-specific interbacterial CDI systems. We will determine if they function in an intra- and/or inter-species manner. We will also determine if the BtpAIB proteins contribute to B. pseudomallei and, if so, if CDI is required for that ability. Understanding how CDI systems function in B. pseudomallei will provide a deeper understanding of the molecular mechanisms underlying the pathogenic strategies used by these complicated pathogens and the information obtained may allow us to exploit CDI systems for the development of new approaches for treating melioidosis and eliminating B. pseudomallei from contaminated environments PUBLIC HEALTH RELEVANCE: Burkholderia pseudomallei, which causes the serious and often fatal disease melioidosis, is an emerging infectious disease pathogen and potential biowarfare agent for which we lack rapid diagnostics, effective therapeutics, and a vaccine. We will test the hypothesis that the B. pseudomallei btpAIB genes encode polymorphic interbacterial competition systems and that they play a role in virulence. Characterization of these systems may allow them to be developed as new types of anti-microbials for treating melioidosis and/or eliminating B. pseudomallei from contaminated environments.