INTERACTION OF LIPID A AND INNATE IMMUNE RECEPTORS IN NEISSERIA INFECTION

奈瑟菌感染中脂质 A 和先天免疫受体的相互作用

• 批准号: 7724210
• 负责人: Gary A Jarvis
• 金额: $ 0.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7724210
• 关键词: Acylation; Chemicals; Clinical; Computer Retrieval of Information on Scientific Projects Database; Disease; Enterobacteriaceae; Epithelial Cells; Funding; Gram-Negative Bacterial Infections; Grant; Heterogeneity; IL8 gene; Immune response; Immunologic Receptors; Infection; Institution; Interleukin-6; Lipid A; Lipids; Lipopolysaccharides; Magnetic Resonance; Mass Fragmentography; Methods; Myeloid Cells; Neisseria; Neisseria gonorrhoeae; Organism; Pathogenesis; Patients; Pelvic Inflammatory Disease; Phosphorylation; Public Health; Relative (related person); Research; Research Personnel; Resources; Role; Sepsis; Severities; Signal Transduction; Source; Structure; Testing; Toxic effect; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Variant; Virulence Factors; base; cytokine; human TNF protein; lipooligosaccharide; monocyte; neutrophil; receptor; response; toll-like receptor 4

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infections due to Neisseria gonorrhoeae and N. meningitidis represent a major public health problem around the world. In patients with Neisserial infections, levels of cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-8 are increased relative to the severity of the clinical disease presentation. Two innate immune receptors, toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells (TREM), which are expressed on monocytes, neutrophils, and mucosal epithelial cells, are stimulated by lipopolysaccharide (LPS) from enteric bacteria and are required for an efficient immune response to Gram-negative bacterial infections. Among the important virulence factors involved in the pathogenesis of Neisserial infections, the lipooligosaccharide (LOS) is believed to be a major component inducing host cytokine responses to the organisms. In particular, several studies have implicated the lipid A portion as the bioactive component of Neisserial LOS. We hypothesize that heterogeneity in the acylation and phosphorylation of the lipid A, both of which have been shown to influence the toxicity of LPS from Escherischia coli, underlies the differential reactivity of Neisserial LOS with TLR4 and TREM resulting in differences in degree to which cytokines are induced during infection. Based on the key role of TLR4 and TREM in the recognition of bacterial LPS, it is apparent that in inappropriate response by these innate immune receptors to LOS signals could have important consequences during Neisserial infections, leading to exaggerated response such as gonococcal pelvic inflammatory disease and meningococcal sepsis. In this proposal, we will test the postulate that natural variation in the lipid A structure within the LOS of different Neisserial strains is the major determinant of the degree to which cytokines are induced during infection. To this end, we will determine the structure of the lipid A molecules from Neisserial strains showing variable stimulation of the TLR4 receptor. We will use chemical, gas chromatography, mass spectrometry, and magnetic resonance methods to determine the structures of the lipid A molecules.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 由于淋病奈瑟氏菌引起的感染和尼林迪氏菌所引起的感染代表了世界上一个主要的公共卫生问题。在奈瑟症感染的患者中，相对于临床疾病表现的严重程度，诸如TNF-ALPHA，IL-1BETA，IL-6和IL-8等细胞因子的水平增加。 两个先天免疫受体，即收费受体4（TLR4）和在髓样细胞上表达的受体（TREM），这些受体在单核细胞，中性粒细胞和粘膜上皮细胞上表达，由脂多糖糖（LP）（LPS）刺激。 在奈瑟氏感染的发病机理中涉及的重要毒力因子中，脂肪含糖（LOS）被认为是诱导宿主细胞因子对生物体的主要成分。 特别是，一些研究将脂质A的一部分视为奈瑟氏LOS的生物活性成分。 我们假设脂质A酰化和磷酸化的异质性，这两者都显示出影响来自埃斯氏菌大肠杆菌LPS的LPS毒性，这是基的基础，它构成了Neisserial LOS与TLR4的差异反应性，以及在感染过程中引起细胞因子的差异而导致的差异。 基于TLR4和TREM在识别细菌LPS中的关键作用，很明显，在这些先天免疫受体对LOS信号的不适当反应中，在奈瑟氏症感染期间可能会产生重要的后果，从而导致夸张的反应，例如巨型造成骨盆炎症性疾病炎症性疾病，男性脑膜癌，脑膜癌塞氏症。 在此提案中，我们将测试假设脂质A在不同奈瑟菌株的LOS内的自然变化是感染过程中细胞因子诱导的程度的主要决定因素。 为此，我们将确定来自奈瑟菌株的脂质A分子的结构，显示TLR4受体的可变刺激。 我们将使用化学，气体色谱，质谱和磁共振方法来确定脂质A分子的结构。