Contact Dependent Growth Inhibition in Burkholderia pseudomallei

鼻疽伯克霍尔德氏菌的接触依赖性生长抑制

• 批准号: 8189371
• 负责人: Peggy A Cotter
• 金额: $ 22.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189371
• 关键词: Acute; Adherence; Aerosols; Alleles; Antibiotics; Australia; Bacteria; Biological Warfare; Bioterrorism; Burkholderia; Burkholderia pseudomallei; C-terminal; Categories; Cells; Communicable Diseases; Data; Development; Diagnostic; Diagnostic tests; Disease; Dose; Emerging Communicable Diseases; Environment; Escherichia coli; Exclusion; Genes; Goals; Gram-Negative Bacteria; Growth; Horizontal Gene Transfer; Immunity; Infection; Laboratory Study; Lung; Mammalian Cell; Mediating; Melioidosis; Modeling; Molecular; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Pathogenesis; Physicians; Play; Proteins; Reporting; Resistance; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Route; Southeastern Asia; Surface; System; Systems Development; Testing; Therapeutic; Toxin; Vaccines; Virulence; fitness; human disease; in vivo; inhibitor/antagonist; killings; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; point-of-care diagnostics; protein function; research study

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.

描述（由申请人提供）：类鼻疽伯克霍尔德氏菌是东南亚和澳大利亚北部特有的革兰氏阴性环境腐生菌，可引起类鼻疽，这是一种严重且往往致命的人类疾病。由于其比以前认识到的更为普遍和/或传播超出既定边界，类鼻疽伯克氏菌是一个严重的新出现的全球传染病问题。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。它所带来的威胁在于其极低的感染剂量、通过气溶胶途径引发感染的能力、对常用抗生素的固有耐药性、缺乏疫苗、缺乏快速诊断测试以及美国医生对这种病毒的不熟悉。疾病。即时诊断的开发、潜在疫苗成分的识别以及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，其中产生称为 CdiA 的大型表面定位蛋白的细菌会抑制在细胞与细胞接触时不产生 CDI 系统的大肠杆菌的生长。我们对类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，并且在杀死靶细胞的 CdiA 蛋白和保护抑制细胞的免疫蛋白区域中具有多态性。类鼻疽杆菌菌株之间的变异性尤其明显。我们建议检验伯克霍尔德杆菌 BtpAIB 蛋白作为等位基因特异性细菌间 CDI 系统发挥作用的假设。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 BtpAIB 蛋白是否对类鼻疽杆菌有贡献，如果有，则该能力是否需要 CDI。了解 CDI 系统如何在类鼻疽杆菌中发挥作用，将有助于更深入地了解这些复杂病原体所使用的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 系统来开发治疗类鼻疽和消灭鼻疽杆菌的新方法。来自受污染环境的假鼻疽 公共卫生相关性： 类鼻疽伯克霍尔德杆菌会导致严重且往往致命的类鼻疽病，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、有效的治疗方法和疫苗。我们将检验假鼻疽杆菌 btpAIB 基因编码多态性细菌间竞争系统并且它们在毒力中发挥作用的假设。这些系统的表征可能使它们能够被开发为新型抗微生物药物，用于治疗类鼻疽和/或消除受污染环境中的类鼻疽杆菌。