BcpAIOB-Mediated CDI and Biofilm Formation in Burkholderia pseudomallei

BcpAIOB 介导的鼻疽伯克霍尔德氏菌中的 CDI 和生物膜形成

• 批准号: 8750147
• 负责人: Peggy A Cotter
• 金额: $ 22.23万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750147
• 关键词: Acute; Aerosols; Alleles; Antibiotic Resistance; Antibiotics; Australia; Bacteria; Biological Assay; Burkholderia; Burkholderia pseudomallei; Cell Death; Cells; Centers for Disease Control and Prevention (U.S.); Communities; Cytoplasm; DNA; Decontaminant; Deletion Mutation; Development; Diagnostic tests; Disease; Dose; Ecology; Emerging Communicable Diseases; Engineering; Environment; Escherichia coli; Foundations; Genes; Genetic Polymorphism; Goals; Growth; Homologous Gene; Human; Immunity; Infection; Knowledge; Laboratory Study; Lung; Mediating; Melioidosis; Methods; Microbe; Microbial Biofilms; Modeling; Molecular; Organism; Pathogenesis; Physicians; Protein Binding; Proteins; Proteobacteria; Reporter; Role; Route; Soil; Southeastern Asia; Surface; System; Testing; Therapeutic; Tissues; Toxic effect; Toxin; Vaccines; Work; biothreat; killings; novel therapeutics; pathogenic bacteria; polypeptide; prevent; protein function; public health relevance; research study; transmission process

DESCRIPTION (provided by applicant): Burkholderia pseudomallei, a motile, Gram-negative, environmental saprotroph, is an emerging infectious disease problem and a previously-weaponinzed CDC Tier 1 select agent. It causes melioidosis in humans, which, in its acute form, can be fatal within days if untreated. Although endemic to southeast Asia and northern Australia, there is evidence that B. pseudomallei is spreading beyond established boundaries. Lack of a vaccine and lack of rapid diagnostic tests, together with the bacterium's low infectious dose and intrinsic antibiotic resistance, underscore the need to develop new therapeutics and new strategies for eliminating B. pseudomallei from contaminated environments, the only reservoir from which transmission to humans occurs. Contact-Dependent Growth Inhibition (CDI) is a phenomenon in which bacteria use the toxic C-terminus of a large surface-exposed exoprotein to inhibit the growth of neighboring bacteria upon cell-cell contact. If present in the cytoplasm, immunity proteins bind to the toxic polypeptides, blocking their catalytic activity and preventing cell death. The toxic C-termini of CDI system exoproteins and the immunity proteins are polymorphic and immunity proteins protect against CDI in an allele-specific manner. It has been suggested that this polymorphism allows bacteria to use CDI systems to discriminate self from non-self as a mechanism for kin selection in microbiological communities, but this hypothesis has not been tested. Whether there is a hierarchy of potencies of different CDI systems and whether the possession of multiple CDI systems is advantageous have also not been tested. We propose experiments to determine if bcpAIOB genes in B. pseudomallei do, as predicted, encode proteins that mediate interbacterial competition and biofilm formation in B. pseudomallei. We will determine if different bcpAIOB alleles encode proteins with different potencies, and if possession of multiple alleles confers a competitive advantage. We will also determine if inter-species CDI occurs and if Burkholderia thailandensis, a non-pathogen that lives in the same ecological niche as B. pseudomallei, can be engineered to produce multiple CDI systems and if this strain can out-compete B. pseudomallei and prevent or destroy B. pseudomallei biofilms. Our results will form the foundation for the exploitation of CDI systems for use as decontaminants and, potentially, therapeutics.

描述（由申请人提供）：Burkholderia pseudomallei，一种运动，革兰氏阴性，环境腐生，是一种新兴的感染性疾病问题，是一种先前沃普诺蛋白的CDC Tier 1 Select Agent。它会导致人类中的黑粒病毒病，如果没有治疗，以急性形式的几天内可能会致命。尽管东南亚和北部澳大利亚的特有，但有证据表明，假单胞菌的传播范围超出了既定的边界。缺乏疫苗和缺乏快速诊断测试，以及该细菌的低感染剂量和内在的抗生素耐药性，强调了开发新的治疗剂和新策略，以消除受污染环境中的假孢菌芽孢杆菌（B. pseudomallei），这是唯一向人类传播的储层。 接触依赖性的生长抑制（CDI）是一种现象，其中细菌使用大型表面暴露的脱蛋白的毒性C末端来抑制细胞细胞接触时邻近细菌的生长。如果存在于细胞质中，则免疫蛋白与毒性多肽结合，阻断其催化活性并预防细胞死亡。 CDI系统的有毒C-末端异蛋白和免疫蛋白是多态和免疫蛋白以特定于等位基因特异性方式预防CDI的多态性和免疫性蛋白。已经提出，这种多态性使细菌可以使用CDI系统将自我与非自身的区别为微生物群落中亲属选择的机制，但是该假设尚未得到检验。是否存在不同CDI系统的效力以及拥有多个CDI系统的效力的层次结构，也没有测试。我们提出了实验，以确定假单胞菌芽孢杆菌中的BCPAIOB基因是否如预测的那样编码介导细菌间竞争和生物膜形成的蛋白质。我们将确定不同的BCPAIOB等位基因是否用不同的能力编码蛋白质，以及是否拥有多个等位基因具有竞争优势。我们还将确定是否发生了种间的CDI，并且可以设计与b。假单胞菌相同的生态生态位，可以设计用于产生多个CDI系统的非病原体，如果这种菌株可以超出兼容型B. pseudomallei并预防或销毁B. pseudomallei Biofilm。我们的结果将为开发CDI系统的基础 用作dectimins，并有可能用作治疗剂。