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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 淋病奈瑟菌和脑膜炎奈瑟菌的感染是世界各地的一个主要公共卫生问题。在奈瑟氏菌感染患者中，细胞因子如肿瘤坏死因子-α、白介素1-β、白介素6和白介素8的水平与临床表现的严重程度相关。表达于单核细胞、中性粒细胞和粘膜上皮细胞上的两种天然免疫受体Toll样受体4(Toll-like Receptor 4，TLR4)和髓样细胞上表达的激活型受体(Trigering Receptor，TREM)，受肠道细菌脂多糖(LPS)的刺激，对革兰氏阴性杆菌感染的有效免疫应答是必需的。在奈瑟氏杆菌感染的致病机制中，脂低聚糖(LOS)被认为是诱导宿主细胞因子应答的主要成分。特别是，几项研究表明，脂类A部分是NeisSerial LOS的生物活性成分。我们推测，脂类A的酰化和磷酸化的异质性，这两者都被证明影响来自大肠杆菌的内毒素的毒性，这是NeisSerial LOS与TLR4和TREM的不同反应基础，导致在感染过程中诱导细胞因子的程度不同。基于TLR4和TREM在细菌内毒素识别中的关键作用，很明显，这些先天免疫受体对LOS信号的不当反应可能在NeisSeries感染过程中产生重要后果，导致过度反应，如淋球菌性盆腔炎和脑膜炎双球菌败血症。在这项提案中，我们将检验这一假设，即不同NeisSeries菌株LOS中脂质A结构的自然变化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NeisSeries菌株的脂A分子结构，这些菌株对TLR4受体具有可变的刺激作用。我们将使用化学、气相色谱、质谱学和磁共振等方法来确定脂类A分子的结构。