The alternative pathway of complement and properdin in Neisseria

奈瑟菌中补体和备解素的替代途径

• 批准号: 8381174
• 负责人: SANJAY RAM
• 金额: $ 24.41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8381174
• 关键词: Alternative Complement Pathway; Anaphylatoxins; Apoptosis; Apoptotic; Bacteria; Binding; Blood Circulation; CD209 gene; Cell Line; Cells; Cervical; Chinese Hamster Ovary Cell; Clinical; Complement; Complement 3 Convertase; Complement Activation; Data; Deposition; Development; Disease; Dolichol; Ectopic Pregnancy; Endometrium; Epithelial Cells; Generations; Genital system; Gonorrhea; Health; Host Defense; Human; Immune; Immune response; Immune system; Individual; Infection; Infertility; Inflammation; Kinetics; Knowledge; Lead; Life; Ligands; Mammalian Oviducts; Mannose; Measures; Morbidity - disease rate; Mutation; Natural Immunity; Necrosis; Neisseria; Neisseria gonorrhoeae; Organism; Pathogenesis; Pathway interactions; Peptides; Peroxidases; Phagocytes; Polysaccharides; Properdin; Protein Family; Proteins; Recombinants; Regulation; Role; Signal Transduction; Source; Staging; Structure; Surface; TLR4 gene; Tryptophan; Vaccines; Woman; adaptive immunity; alternative pathway complement C3 convertase; arm; base; combat; complement pathway; complement system; cytotoxicity; glycosylation; gonorrhea vaccine; killings; lipooligosaccharide; macrophage; male; mannose receptor; mutant; neutrophil; novel; pathogen; phosphoethanolamine; porin; protein function; response; sexual encounter; therapy development; transmission process; uptake; vaccine candidate

The alternative pathway (AP) of complement (C) forms a key arm of innate immune defenses against Neisseria gonorrhoeae (Ng) infections. Properdin (P) is the only known positive regulator of C. The central theme of this proposal is to understand the role of P in Ng pathogenesis. The best known function of P is to stabilize AP C3 convertases and enhance C3 deposition. A novel mechanism of AP activation whereby P binds directly to surfaces (including Ng) and inifiates AP activafion has recently been described. In Aim 1 we will measure P in cervical secretions and correlate P levels with PMN (the major reservoir for P) influx and define the role of P in activating the AP in the context of cervical secretions. Our collaborators have developed a pepfide mimitope Ng vaccine directed against a conserved Ng lipooligosaccharide (LOS) structure. We will examine the role of P in AP amplification of C3 deposited by this vaccine candidate Ab. P also binds to live intact macrophages (MP) and a diverse array of apoptotic and necrotic cell lines. We hypothesize that P bound to Ng bridges bacteria to cells. We have preliminary evidence that the ligand for P on Ng is PorB. In Aim 2 we will confinn the identity of PorB as the Ng ligand for P and define the thrombospondin type 1 repeat (TSR) domain in P (P is composed almost enfirely of six TSR domains) that binds to Ng. Further, we will study the role of P in the association of Ng with MPs and viable cervical epithelial cells and cervical epithelial cells at various stages of apoptosis and necrosis. P possesses novel Cmannosyl substitufions at 14 of its tryptophan residues, making it the most heavily C-mannosylated human protein known. In Aim 3, we will examine the role of the mannosyl residues in binding to, and activafing the AP on Ng. P binds to normal (nonapoptofic) MPs and a prior study has shown that C-mannosylated TSRderived peptides bind MPs and enhance LPS-induced cytotoxicity. We hypothesize that mannose residues on P engage mannose receptors (e.g. MR and DC-SIGN) on MPs and that the P-MP interaction could decrease the TLR-4 dependant LOS signaling threshold. We will characterize the role of P mannosylafion in binding to MPs and in modulating TLR4-dependent signaling by LOS.

补体的替代途径（c）构成了先天免疫防御的关键部门 淋病奈瑟氏菌感染（NG）感染。 Pohordin（P）是C的唯一已知的阳性调节剂。 该建议的主题是了解P在NG发病机理中的作用。 P的最著名功能是 稳定AP C3转化酶并增强C3沉积。 AP激活的一种新型机制P 最近已经描述了直接与表面（包括NG）结合（包括NG），并且已描述了AP Activafion。在目标1中我们 将测量宫颈分泌物中的P，并将P水平与PMN（P的主要库）涌入和 定义P在宫颈分泌的背景下激活AP的作用。我们的合作者有 开发了针对保守的NG脂肪糖（LOS）的PEPFIDE MIMIMITOPE NG疫苗 结构。我们将研究P该疫苗候选AB沉积的C3 AP扩增的作用。 p 还结合了活的完整巨噬细胞（MP）以及各种凋亡和坏死细胞系。我们 假设P结合NG将细菌与细胞结合在一起。我们有初步的证据表明P的配体P 在NG上是PORB。在AIM 2中，我们将把PORB的身份确定为P的NG配体，并定义 p中的1型血小板素1型重复（TSR）域（p几乎由六个TSR域组成） 与Ng结合。此外，我们将研究P在NG与MPS和可行宫颈关联中的作用 在凋亡和坏死的各个阶段，上皮细胞和宫颈上皮细胞。 P具有新颖的cmannosyl 其色氨酸残基的14个取代，使其成为最严重的c-mannosylation人 蛋白质已知。在AIM 3中，我们将研究甘露糖基残基在结合并激活的作用 ap on Ng。 P与正常（非丙法花）MPS结合，并且先前的研究表明C-甘露糖基化的TSRDERDED 肽结合MP并增强LPS诱导的细胞毒性。我们假设Mannose残留物 在P上吸引MPS上的甘露糖受体（例如MR和DC-SIGN），并且P-MP相互作用可以 降低TLR-4依赖性LOS信号传导阈值。我们将表征p甘露叶甘诺酯在 与MPS结合并通过LOS调节TLR4依赖性信号。