Contact Dependent Growth Inhibition in Burkholderia pseudomallei

描述(申请人提供)：假鼻疽伯克霍尔德氏菌是一种革兰氏阴性环境腐生菌，特有于东南亚和澳大利亚北部，导致类鼻疽病，这是一种严重的、通常是致命的人类疾病。由于假鼻疽的流行程度远远超过以往的认识和/或超越既定的边界，假鼻疽是一个严重的新出现的全球性传染病问题。它也是一种潜在的生物恐怖主义因子，已被归类为NIAID B类优先病原体。它的威胁突出表现在其极低的感染剂量、通过气雾剂途径引发感染的能力、对常用抗生素的内在抵抗力、缺乏疫苗、缺乏快速诊断测试以及美国医生对这种疾病的不熟悉。发展护理点诊断、确定潜在的疫苗成分和开发新的治疗方法仍然是高度优先的目标。接触依赖性生长抑制(CDI)是在特定的大肠杆菌菌株中发现的一种现象，在这种现象中，产生一种名为CDIA的大型表面定位蛋白的细菌在细胞与细胞接触时抑制不产生CDI系统的大肠杆菌的生长。我们对假鼻疽杆菌的初步研究表明，CDI系统在革兰氏阴性细菌中广泛存在，并且它们在杀死靶细胞的CDIA蛋白和保护抑制细胞的免疫蛋白区域具有多态。变异性在假鼻疽杆菌菌株中尤其明显。我们建议检验伯克霍尔德氏菌BtpAIB蛋白作为等位基因特异性的细菌间CDI系统的假设。我们将确定它们是否以种内和/或种间的方式发挥作用。我们还将确定BtpAIB蛋白是否对假鼻疽杆菌有贡献，如果是，是否需要CDI来实现这一能力。了解CDI系统如何在假鼻疽杆菌中发挥作用，将有助于我们更深入地了解这些复杂病原体所使用的致病策略背后的分子机制，所获得的信息可能会使我们利用CDI系统来开发治疗类鼻疽病和从受污染的环境中消除假鼻疽杆菌的新方法。 公共卫生相关性： 类鼻疽伯克霍尔德氏菌是一种新出现的传染病病原体，也是一种潜在的生物制剂，目前缺乏快速诊断、有效的治疗方法和疫苗。我们将检验假丝核杆菌btpAIB基因编码多态的细菌间竞争系统以及它们在毒力中发挥作用的假设。这些系统的特性可能会使它们成为治疗类鼻疽病和/或从受污染的环境中消除假鼻疽的新型抗微生物药物。

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.