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: 8624652
• 负责人: Michael Stephen Trent
• 金额: $ 38.08万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624652
• 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.

描述（由申请人提供）：细菌组装与周围环境接触的显著表面结构。其中一种结构是被称为脂多糖（LPS）的糖脂，它覆盖在革兰氏阴性细菌的表面。LPS通过其称为脂质A的脂质锚锚定在细菌细胞上。脂质A通过内膜细胞质面的高度保守途径合成。随后加入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，潜在的酶修饰LPS结构，有助于LPS结构的多样性。在大多数情况下，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，这些修饰可以通过改变哺乳动物先天免疫受体TLR 4-MD 2对LPS的识别来对疾病产生深远的影响。此外，LPS结构的改变可直接影响外膜渗透屏障和细菌对宿主抗微生物肽的抗性。本提案的总体目标是阐明两种致病生物幽门螺杆菌和空肠弯曲菌修饰其LPS结构的分子机制以及这些修饰在毒力中的作用。虽然相关，这些病原体已经进化出独特的修改机制，可能是适应其特定的生态位。本提案的具体目标是：（1）幽门螺杆菌LPS修饰机制的表征;（2）空肠弯曲菌中脂质A修饰的表征;和（3）幽门螺杆菌和空肠弯曲菌LPS重塑对宿主先天免疫应答的影响。完成以下目标将直接有助于我们理解LPS修饰机制如何影响发病机制。最后，从这项工作中将出现疫苗开发的新途径和产生可用作潜在佐剂和/或LPS拮抗剂的工程化LPS结构的能力。