Bacterial Surface Structures of Helicobacter Pylori and Campylobacter Jejuni

幽门螺杆菌和空肠弯曲菌的细菌表面结构

• 批准号: 8240468
• 负责人: Michael Stephen Trent
• 金额: $ 37.96万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240468
• 关键词: Adjuvant; Animals; Antimicrobial Resistance; Bacteria; Campylobacter; Campylobacter jejuni; Cell Membrane Permeability; Cells; Characteristics; Communicable Diseases; Complex; Disease; Engineering; Environment; Enzymes; Face; Flagella; Glycolipids; Goals; Gram-Negative Bacteria; Helicobacter; Helicobacter pylori; Helicobacter pylori lipopolysaccharide; Human; Immune response; Immune system; Immunologic Receptors; Lipid A; Lipids; Lipopolysaccharides; Membrane; Modification; Molecular; O Antigens; Oligosaccharides; Organism; Pathogenesis; Pathway interactions; Play; Polysaccharides; Process; Property; Proteobacteria; Recycling; Resistance; Role; Septic Shock; Stress; Structure; Surface; System; TLR4 gene; Toll-like receptors; Transferase; Virulence; Work; antimicrobial peptide; bacterial resistance; cell envelope; human disease; lipooligosaccharide; novel; pathogen; periplasm; phosphoethanolamine; public health relevance; small molecule; trafficking; vaccine development

DESCRIPTION (provided by applicant): Bacteria assemble remarkable surface structures that interface with their surrounding environment. One such structure is the glycolipid known as lipopolysaccharide (LPS) that covers the surface of gram-negative bacteria. LPS is anchored to the bacterial cell by its lipid anchor known as lipid A. Lipid A is synthesized via a highly conserved pathway at the cytoplasmic face of the inner membrane. This is followed by addition of the core oligosaccharide and transport of the molecule across the inner membrane. The O-antigen polysaccharide is ligated to the core-lipid A in the periplasm completing LPS assembly. During the trafficking of LPS to the bacterial surface, latent enzymes modify the LPS structure contributing towards the diversity seen in LPS structure. For the most part, these enzymes target the lipid A anchor and the inner core oligosaccharide domains of the molecule. Since the lipid A is the bioactive component of LPS, these modifications can have a profound impact on disease, by altering LPS recognition by the mammalian innate immune receptor TLR4- MD2. Additionally, alteration of the LPS structure can directly impact the outer membrane permeability barrier, and bacterial resistance to host antimicrobial peptides. The overall objective of this proposal is to unravel the molecular mechanisms by which two pathogenic organisms, Helicobacter pylori and Campylobacter jejuni, modify their LPS structure and the role these modifications play in virulence. Although related, these pathogens have evolved unique modification machinery perhaps adapted for their specific ecological niche. The specific aims of the current proposal are: (1) characterization of Helicobacter pylori LPS modification machinery; (2) characterization of lipid A modifications in Campylobacter jejuni; and (3) impact of Helicobacter and Camyplobacter LPS remodeling on the host innate immune response. The completion of the Aims below will directly contribute to our understanding of how LPS modification machinery impacts pathogenesis. Finally, from this work will come new avenues of vaccine development and the ability to generate engineered LPS structures that could serve as potential adjuvants and/or LPS antagonists. PUBLIC HEALTH RELEVANCE: Gram-negative bacteria are responsible for a number of human infectious diseases. On the surface of these bacteria is a molecule called lipopolysaccharide or LPS that activates the human immune system. Bacteria modify their LPS structure which directly impacts disease. This proposal will help determine how bacteria associated with human disease modify their LPS structure possibly leading to novel therapies.

描述（由申请人提供）：细菌组装出与其周围环境相接触的显着表面结构。其中一种结构是糖脂，称为脂多糖（LPS），覆盖革兰氏阴性细菌的表面。 LPS 通过其称为脂质 A 的脂质锚定物锚定在细菌细胞上。脂质 A 通过内膜细胞质面的高度保守途径合成。随后添加核心寡糖并将分子转运穿过内膜。 O 抗原多糖与周质中的核心脂质 A 连接，完成 LPS 组装。在 LPS 运输到细菌表面的过程中，潜在的酶会改变 LPS 结构，从而导致 LPS 结构的多样性。大多数情况下，这些酶靶向脂质 A 锚和分子的内核寡糖结构域。由于脂质 A 是 LPS 的生物活性成分，因此这些修饰可以通过改变哺乳动物先天免疫受体 TLR4-MD2 对 LPS 的识别来对疾病产生深远的影响。此外，LPS结构的改变可以直接影响外膜渗透屏障和细菌对宿主抗菌肽的耐药性。该提案的总体目标是揭示幽门螺杆菌和空肠弯曲菌这两种病原微生物改变其 LPS 结构的分子机制以及这些修饰在毒力中所起的作用。尽管相关，但这些病原体已经进化出独特的修饰机制，可能适合其特定的生态位。当前提案的具体目标是：（1）幽门螺杆菌LPS修饰机制的表征； (2) 空肠弯曲杆菌中脂质A修饰的表征； (3)螺杆菌和弯曲杆菌LPS重塑对宿主先天免疫反应的影响。完成以下目标将直接有助于我们了解 LPS 修饰机制如何影响发病机制。最后，这项工作将带来疫苗开发的新途径以及产生可作为潜在佐剂和/或 LPS 拮抗剂的工程化 LPS 结构的能力。 公共卫生相关性：革兰氏阴性菌是许多人类传染病的原因。这些细菌的表面有一种称为脂多糖或 LPS 的分子，可以激活人体免疫系统。细菌改变其脂多糖结构，直接影响疾病。该提案将有助于确定与人类疾病相关的细菌如何改变其 LPS 结构，从而可能导致新的疗法。