Bacterial Lipopolysaccharide Structure

细菌病原体已经进化出对环境变化的适应性反应，当它们 从外部存储库输入主机。这些反应包括对细菌细胞膜的修饰 这增强了定植能力，扩散到不同的组织，并避开宿主的正常防御。这个 抗吞噬胶囊、粘附性菌毛等辅助结构的合成及新整合体 膜蛋白是与宿主相关的表面修饰的例子。对基本细胞的修饰 膜成分，如脂A[脂多糖的疏水膜锚]，是 对发病机制很重要。这些和其他毒力相关的适应通常是协调调节的 通过响应环境变化的双分量信号传感和传输系统(例如， 温度、渗透压、pH和特定离子浓度)。在初步研究中，我们发现 在生长过程中，为了适应温度的变化，从21摄氏度到37摄氏度，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合成了独特的类脂A结构。这些 环境调节的类脂A结构赋予对阳离子抗菌肽(CAP)的抵抗力， 并促进改变的宿主炎症反应。因此，脂类A的温度依赖性变化 进入哺乳动物宿主时的结构(内毒素含量较低)可能代表一种发病机制 耶尔西尼亚亚族共有的策略。 这一建议包含定义和阐明合成的机制的实验。 鼠疫耶尔森氏菌受环境调节的类脂A结构，并确定其类脂A结构。 图拉氏方济氏菌和假鼻疽伯克霍尔德氏菌，潜在的生物恐怖主义病原体。此外，这个角色 对这些特定的脂蛋白A结构在影响宿主先天免疫系统中的作用进行了研究。 演出现场(S)(组织、市、州) 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 命名项目中的组织角色 华盛顿州西雅图华盛顿大学罗伯特·K·恩斯特 华盛顿州西雅图华盛顿大学塞缪尔·I·米勒联合调查员 约瑟夫·辛尼布施落基山实验室，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_

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_