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: 8427395
• 负责人: Michael Stephen Trent
• 金额: $ 35.74万
• 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/8427395
• 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）：细菌组装了与周围环境界面的显着表面结构。其中一种结构是覆盖在革兰氏阴性菌表面的脂多糖（LPS）。脂质A是通过内膜细胞质面高度保守的途径合成的，脂质A是通过内膜细胞质面高度保守的途径合成的。接下来是添加核心寡糖和分子穿过内膜的运输。o抗原多糖与外周质核心脂质A连接，完成LPS组装。在将LPS运输到细菌表面的过程中，潜伏酶改变了LPS的结构，从而导致了LPS结构的多样性。在大多数情况下，这些酶靶向脂质A锚点和分子的核心低聚糖结构域。由于脂质A是脂多糖的生物活性成分，这些修饰可以通过改变哺乳动物先天免疫受体TLR4- MD2对脂多糖的识别而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的通透性屏障，以及细菌对宿主抗菌肽的耐药性。本研究的总体目标是揭示幽门螺杆菌和空肠弯曲杆菌这两种致病生物改变其LPS结构的分子机制，以及这些改变在毒力中的作用。虽然相关，但这些病原体已经进化出独特的修饰机制，可能适应其特定的生态位。当前提案的具体目的是：(1)表征幽门螺杆菌LPS修饰机制；(2)空肠弯曲杆菌脂质A修饰的研究；(3)幽门螺杆菌和弯曲杆菌LPS重塑对宿主先天免疫应答的影响。以下目标的完成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，这项工作将带来疫苗开发的新途径和产生工程LPS结构的能力，这些结构可以作为潜在的佐剂和/或LPS拮抗剂。