Bacterial Lipopolysaccharide Structure

细菌脂多糖结构

• 批准号: 7637607
• 负责人: Robert K Ernst
• 金额: $ 36.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637607
• 关键词: Acyltransferase; Adhesives; Aerobic; Affect; Anabolism; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Authorization documentation; Bacteria; Bioterrorism; Burkholderia pseudomallei; Calcium; Cell membrane; Cells; Cities; Class; Condition; Culture Media; Disclosure; Environment; Enzymes; Escherichia coli; Fatty Acids; Fimbria of hippocampus; Fleas; Francisella tularensis; Gas Chromatography; Genes; Growth; Homologous Gene; Human Resources; Immune system; Individual; Inflammation; Inflammatory Response; Instruction; Integral Membrane Protein; Ions; Iron; Laboratories; Last Name; Life Cycle Stages; Lipid A; Lipopolysaccharides; Location; Magnesium; Mammals; Mass Spectrum Analysis; Membrane; Modification; Mus; Mutation; Names; Osmotic Pressure; Palmitates; Pathogenesis; Pilum; Polymyxin Resistance; Principal Investigator; Regulator Genes; Research Personnel; Resistance; Role; Signal Transduction; Structure; Surface; System; Temperature; Testing; Tissues; Universities; Virulence; Washington; Yersinia; Yersinia pestis; aminoarabinose; antimicrobial peptide; capsule; cell envelope; environmental change; mouse model; pathogen; performance site; programs; research study; response; tissue culture

Bacterial pathogens have evolved adaptive responses to the environmental changes encountered when they enter a host from an external reservoir. These responses include modifications of the bacterial cell envelope that enhance the ability to colonize, spread to different tissues, and avoid the hosts' normal defenses. The synthesis of accessory structures such as antiphagocytic capsules, adhesive fimbriae, and new integral membrane proteins are examples of host-associated surface modifications. Modifications to essential cell membrane components such as lipid A [the hydrophobic membrane anchor of lipopolysaccharide (LPS)], are important for pathogenesis. These and other virulence-related adaptations are often coordinately regulated via two-component signal sensing and transduction systems that respond to environmental changes (e.g., of temperature, osmotic pressure, pH, and concentrations of specific ions). In preliminary studies, we found that in response to a change of temperature during growth, from 21¿C to 37¿C, to mimic the bacterial "flea to mammal" (or external environment to mammal) life cycle, Yp synthesized unique lipid A structures. These environmentally-regulated lipid A structures conferred resistance to cationic antimicrobial peptides (CAP), and promote altered host inflammatory responses. Thus, temperature-dependent alteration of lipid A structure (to a less endotoxic form) upon entry into the mammalian host may represent a pathogenesis strategy common to the Yersiniae. This proposal contains experiments to define and to elucidate the mechanism of the synthesis of environmentally-regulated lipid A structures from Yersinia pestis, and to also define the lipid A structures of Francisella tularensis and Burkholderia pseudomallei, potential agents of bioterrorism. In addition, the role of these specific lipid A structures in affecting the innate immune system of the host will be determined. PERFORMANCE SITE(S) (organization, city, state) KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Robert K. Ernst University of Washington, Seattle, WA PI Samuel I. Miller University of Washington, Seattle, WA Co-investigator Joseph Hinnebusch Rocky Mountain Laboratories, Hamilton, MT Collaborator Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No Pl-l.q _CI_ (I_,,_ N_ff1"l _nrm P_n_

细菌病原体已经进化出对遇到的环境变化的适应性反应。 从外部水库进入宿主。这些反应包括细菌细胞包膜的修饰 增强定殖、扩散到不同组织并避开宿主正常防御的能力。这 辅助结构的合成，例如抗吞噬细胞胶囊、粘附菌毛和新的积分 膜蛋白是宿主相关表面修饰的例子。对必需细胞的修饰 膜成分，如脂质 A [脂多糖 (LPS) 的疏水膜锚]，是 对发病机制很重要。这些和其他毒力相关的适应通常受到协调调节 通过响应环境变化（例如， 温度、渗透压、pH 值和特定离子的浓度）。在初步研究中，我们发现 响应生长过程中的温度变化（从 21°C 到 37°C），以模仿细菌“跳蚤 哺乳动物”（或哺乳动物的外部环境）生命周期中，Yp 合成了独特的脂质 A 结构。这些 环境调节的脂质 A 结构赋予对阳离子抗菌肽 (CAP) 的抗性， 并促进宿主炎症反应的改变。因此，脂质 A 的温度依赖性改变 进入哺乳动物宿主后的结构（内毒性较小的形式）可能代表一种发病机制 耶尔森菌共有的策略。 该提案包含定义和阐明合成机制的实验 鼠疫耶尔森氏菌的环境调节脂质 A 结构，并定义了鼠疫耶尔森氏菌的脂质 A 结构 土拉弗朗西斯菌和鼻疽伯克霍尔德菌是生物恐怖主义的潜在媒介。此外，角色 将确定这些特定脂质 A 结构对宿主先天免疫系统的影响。 绩效站点（组织、城市、州） 关键人员。请参阅说明。根据需要使用延续页面以如下所示的格式提供所需信息。 从首席研究员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称 组织在项目中的角色 罗伯特·恩斯特 (Robert K. Ernst) 华盛顿大学，西雅图，华盛顿州 Samuel I. Miller 华盛顿大学，西雅图，华盛顿州 联合研究员 Joseph Hinnebusch 落基山实验室，汉密尔顿，MT 合作者 披露许可声明。仅适用于 SBIR/STTR。请参阅说明。 [] 是 [] 否 Pl-l.q _CI_ (I_,,_ N_ff1"l _nrm P_n_