Interaction of LOS and Innate Immunity in Neisseria Infection

奈瑟菌感染中 LOS 与先天免疫的相互作用

• 批准号: 9140859
• 负责人: Gary A Jarvis
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140859
• 关键词: Active Sites; Acylation; Affect; Alkaline Phosphatase; Anabolism; Antibiotic Resistance; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Binding; Blood; Blood Vessels; Caspase; Cause of Death; Cell Culture Techniques; Cells; Cervical; Cessation of life; Cleaved cell; Complement; Complex; Conjugate Vaccines; Cytolysis; Data; Developed Countries; Development; Disease; Down-Regulation; Ectopic Pregnancy; Elements; Environment; Enzymes; Epithelial; Epithelial Cells; Excision; Extravasation; Failure; Feedback; Female; Fever; Functional disorder; General Population; Genetic; Gonorrhea; Gram-Negative Bacteria; HIV; HIV-1; Headache; Healthcare; Human; Hydrolase; Immune; Immune response; Immune system; Incidence; Individual; Infection; Infertility; Inflammatory; Inflammatory Response; Investigation; Knowledge; Laboratories; Lead; Leukocytes; Lipid A; Lipids; Mammalian Cell; Mediating; Membrane; Meningitis; Meningococcal Infections; Military Personnel; Mission; Modeling; Molecular; Multi-Drug Resistance; Mus; Nasopharynx; Natural Immunity; Nausea; Neck; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Neuraxis; New Agents; Oligosaccharides; Organ; Organism; Patient Care; Pelvic Inflammatory Disease; Persons; Phagocytosis; Phenotype; Phosphorylation; Play; Polymyxin B; Polysaccharides; Population; Predisposition; Proteins; Public Health; Publishing; Reporting; Research; Resistance; Resistance development; Risk Behaviors; Role; Seizures; Sepsis; Septic Shock; Services; Sexually Transmitted Diseases; Signal Transduction; Structure; Study models; Symptoms; TLR4 gene; TNF gene; Testing; Therapeutic; Therapeutic Agents; Thinking; Vaccination; Vaccines; Vascular Endothelial Cell; Veterans; Whole Blood; Woman; Work; acyl group; aged; bactericide; base; brain cell; cell type; chronic pain; cytotoxicity; deafness; effective therapy; high risk; inhibitor/antagonist; inorganic phosphate; killings; limb amputation; lipooligosaccharide; men; mental state; new therapeutic target; novel strategies; novel therapeutics; novel vaccines; pathogen; public health relevance; receptor; resistant strain; response; small molecule inhibitor; transmission process; uptake

 DESCRIPTION (provided by applicant): Infections due to the Gram-negative bacteria Neisseria meningitidis and N. gonorrhoeae represent major public health problems around the world. Meningococcal infections total 0.5-1.2 million and cause death of 50,000-135,000 individuals annually worldwide. Infections by N. meningitidis can present with a range of symptoms including sudden onset of fever, headache, stiff neck, nausea, and alterations in mental state. The bacteria primarily infect the central nervous system causing cerebrospinal meningitis, but can also cause disseminated disease leading to an overwhelming inflammatory response known as sepsis that can result in vascular leakage, failure in multiple organs, and death or long term sequelae including amputation of limbs, deafness, and seizures. Declines in meningococcal disease have occurred in the last decade in many developed countries due in part to use of polysaccharide-protein conjugate vaccines to specific serogroups of N. meningitidis, although the vaccines are not 100% effective and do not provide protection against all serogroups or strains. In addition, two new vaccines for serogroup B disease have been approved recently, however approval is only for persons aged 10-25 years, and unanswered questions exist regarding efficacy. Paradoxically, N. meningitidis infects the nasopharynx of 8-20% of the population without causing disease. There are an estimated 106 million new cases of sexually transmitted gonococcal infections worldwide each year. Those most affected by the disease are women in whom infections are often asymptomatic. From 10- 20% of infected women suffer from pelvic inflammatory disease that can cause chronic pain, infertility, and ectopic pregnancy. Importantly, a growing number of studies have shown that gonococcal infection can facilitate the transmission of HIV. The lack of a vaccine and increasing number of strains of N. gonorrhoeae that are resistant to treatment with antibiotics have heightened the possibility of loss of control of the transmission of gonorrhea. Our work has focused on understanding the interactions of a major component of the bacterial membrane, the lipooligosaccharide (LOS), with the human immune system. Preformed components of what is termed the "innate immune system" are the first line of defense in protection against Gram-negative bacteria such as Neisseria. We have found that the ability of Neisseria to induce a feedback down-regulation of the innate immune response is positively correlated with the inflammatory potential of the bacteria which in turn is mediated by the expression of particular molecular substituents on the LOS. Our data also show that certain elements of the LOS structure assist the bacteria in evading lysis by the complement cascade in the blood and recognition by human antibodies that facilitate phagocytosis by white blood cells. These data are supported by the findings from several other laboratories in the field and previous results from our own research. This project is focused on testing and developing potential new therapeutic agents that will inhibit the bioactivity of the LOS by enzymatic removal of phosphate and acyl groups on the lipid and by inhibiting the genetic expression or competing for binding specifically to the active site of LOS biosynthetic enzymes. In addition, we will exten our observations regarding the inflammatory potential of the LOS and invasive ability of the Neisseria to interactions with an extensive set of relevant cell types that play a role in Neisseri infections. We will study models of infection in whole blood, in nasopharyngeal, cervical, and endothelial epithelial cells, monocytic cells, vascular endothelial cells, and brain cells, and analyze the bioactivity of LOS when inside of cells. We expect that the results will demonstrate the validity of new therapeutic targets, identify and develop potential new agents for the treatment of Neisseria infections, and increase our understanding of the complex relationship between these uniquely human pathogens and the innate immune system that enables the bacteria to cause disease.

 描述（由申请人提供）： 革兰氏阴性菌脑膜炎奈瑟菌和淋病奈瑟菌引起的感染是世界各地的主要公共卫生问题。全球每年脑膜炎球菌感染总数为 0.5-120 万，导致 50,000-135,000 人死亡。脑膜炎奈瑟菌感染可出现一系列症状，包括突然发烧、头痛、颈部僵硬、恶心和精神状态改变。这些细菌主要感染中枢神经系统，引起脑脊髓膜炎，但也可引起播散性疾病，导致严重的炎症反应，称为败血症，可导致血管渗漏、多个器官衰竭、死亡或长期后遗症，包括截肢、耳聋和癫痫发作。过去十年来，许多发达国家的脑膜炎球菌疾病有所减少，部分原因是针对脑膜炎奈瑟氏球菌特定血清群使用了多糖蛋白结合疫苗，尽管这些疫苗并非 100% 有效，并且不能针对所有血清群或菌株提供保护。此外，两种针对B血清群疾病的新疫苗最近已获得批准，但批准仅适用于10-25岁的人群，且功效方面存在悬而未决的问题。矛盾的是，脑膜炎奈瑟菌感染了 8-20% 人口的鼻咽部，但并未引起疾病。 据估计，全球每年新增性传播淋球菌感染病例 1.06 亿例。受该疾病影响最严重的是女性，她们的感染通常无症状。 10-20% 的受感染女性患有盆腔炎，可能导致慢性疼痛、不孕和宫外孕。重要的是，越来越多的研究表明，淋球菌感染可以促进艾滋病毒的传播。由于缺乏疫苗以及对抗生素治疗产生耐药性的淋病奈瑟菌菌株数量不断增加，增加了淋病传播失控的可能性。 我们的工作重点是了解细菌膜的主要成分脂寡糖 (LOS) 与人体免疫系统的相互作用。所谓的“先天免疫系统”的预制组件是抵御奈瑟菌等革兰氏阴性细菌的第一道防线。我们发现奈瑟菌诱导先天免疫反应反馈下调的能力与细菌的炎症潜力呈正相关，而细菌的炎症潜力又由 LOS 上特定分子取代基的表达介导。我们的数据还表明，LOS 结构的某些元件有助于细菌逃避血液中补体级联的裂解以及促进白细胞吞噬的人类抗体的识别。这些数据得到了该领域其他几个实验室的研究结果以及我们自己研究的先前结果的支持。 该项目的重点是测试和开发潜在的新治疗剂，通过酶法去除脂质上的磷酸盐和酰基，并通过抑制基因表达或竞争与LOS生物合成酶的活性位点特异性结合来抑制LOS的生物活性。此外，我们还将对 LOS 的炎症潜力和奈瑟氏菌的侵袭能力的观察扩展到与在奈瑟氏菌感染中发挥作用的广泛相关细胞类型的相互作用。我们将研究全血、鼻咽、宫颈、内皮上皮细胞、单核细胞、血管内皮细胞和脑细胞的感染模型，并分析LOS在细胞内部的生物活性。我们期望这些结果将证明新治疗靶点的有效性，识别和开发治疗奈瑟菌感染的潜在新药，并加深我们对这些独特的人类病原体与使细菌引起疾病的先天免疫系统之间复杂关系的理解。