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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 淋病奈瑟菌和脑膜炎奈瑟菌引起的感染是世界各地的一个重大公共卫生问题。在奈瑟球菌感染患者中，细胞因子（例如 TNF-α、IL-1β、IL-6 和 IL-8）的水平相对于临床疾病表现的严重程度有所增加。 两种先天免疫受体，Toll 样受体 4 (TLR4) 和骨髓细胞表达的触发受体 (TREM)，它们表达于单核细胞、中性粒细胞和粘膜上皮细胞，受到肠道细菌脂多糖 (LPS) 的刺激，并且是必需的对革兰氏阴性细菌感染产生有效的免疫反应。 在涉及奈瑟氏球菌感染发病机制的重要毒力因子中，脂寡糖（LOS）被认为是诱导宿主细胞因子对生物体反应的主要成分。 特别是，一些研究表明脂质 A 部分是奈瑟氏菌 LOS 的生物活性成分。 我们假设脂质 A 的酰化和磷酸化的异质性（两者均已被证明会影响大肠杆菌 LPS 的毒性）是奈瑟氏菌 LOS 与 TLR4 和 TREM 的差异反应性的基础，导致细胞因子的作用程度存在差异。感染过程中诱发。 基于 TLR4 和 TREM 在识别细菌 LPS 中的关键作用，很明显，这些先天免疫受体对 LOS 信号的不当反应可能会在奈瑟球菌感染期间产生重要后果，导致过度反应，例如淋菌性盆腔炎和脑膜炎球菌败血症。 在本提案中，我们将测试以下假设：不同奈瑟氏球菌菌株 LOS 内脂质 A 结构的自然变异是感染期间诱导细胞因子程度的主要决定因素。 为此，我们将确定奈瑟氏菌菌株的脂质 A 分子的结构，这些菌株显示出对 TLR4 受体的不同刺激。 我们将使用化学、气相色谱、质谱和磁共振方法来确定脂质 A 分子的结构。