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感染是世界范围内的主要公共卫生问题，脑膜炎球菌感染总数为 0.5-120 万，每年导致 50,000-135,000 人死亡。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。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，许多发达国家都出现了脑膜炎球菌病，部分原因是针对特定的奈瑟氏球菌血清群使用了多糖-蛋白结合疫苗。脑膜炎球菌疫苗虽然不是 100% 有效，并且不能针对所有血清群或菌株提供保护。此外，最近批准了两种针对 B 血清群疾病的新疫苗，但批准仅适用于 10-25 岁的人群，且尚未得到答复。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。全世界每年都会出现新的性传播淋球菌感染病例，感染该病的女性往往无症状，其中 10-20% 的感染女性患有盆腔炎，可导致慢性疼痛、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。疫苗的缺乏以及耐药性淋病奈瑟菌菌株的数量不断增加。抗生素治疗可能会导致淋病传播失控。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”是针对革兰氏阴性细菌（例如奈瑟氏菌）的第一道防线。我们发现奈瑟氏菌诱导先天免疫反应反馈下调的能力呈正相关。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和识别。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的先前研究结果的支持，该项目的重点是测试和开发潜在的新治疗剂，以抑制通过酶去除脂质上的磷酸盐和酰基以及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研究 LOS 的生物活性。此外，我们将扩展对 LOS 炎症潜力的观察。以及奈瑟菌与一系列在奈瑟菌感染中发挥作用的相关细胞类型相互作用的侵袭能力。我们将研究全血、鼻咽、宫颈和口腔中的感染模型。内皮上皮细胞、单核细胞、血管内皮细胞和脑细胞，并分析 LOS 在细胞内部的生物活性，我们期望结果将证明新治疗靶点的有效性，识别和开发潜在的新药物治疗。奈瑟氏菌感染，并增加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。