Experimental and human protective immunity to Neisseria gonorrhoeae

对淋病奈瑟菌的实验和人体保护性免疫力

• 批准号: 8318892
• 负责人: Peter A. Rice
• 金额: $ 40.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318892
• 关键词: Animals; Antibodies; Antibody Formation; Antibody Repertoire; Binding; Binding Proteins; Blocking Antibodies; Chlamydia Infections; Complement; Complement 3b; Complement 4b; Complement Factor H; Development; Epitopes; Experimental Models; Exposure to; Failure; Gonorrhea; HIV Infections; Human; Immune; Immune System Part; Immune response; Immunity; Inbred BALB C Mice; Infection; Infection prevention; Infertility; Lead; Measurement; Measures; Mediating; Membrane Proteins; Modeling; Mus; Natural Immunity; Neisseria gonorrhoeae; Oligosaccharides; Pathway interactions; Pelvic Inflammatory Disease; Peptides; Predisposition; Proteins; Resistance to infection; Respondent; Role; Sexual Partners; Sexually Transmitted Diseases; Simulate; Site; Specificity; Symptoms; System; Testing; Transgenic Mice; Urethra; Vaccinated; Vaccination; Vaccines; Woman; adaptive immunity; bactericide; complement 4b-binding protein; efficacy testing; human subject; immunogenic; immunogenicity; in vitro activity; in vivo; killings; lipooligosaccharide; male; microbial alkaline proteinase inhibitor; mouse model; pathogen; prevent; research study; therapy development; vaccine candidate; vaccine efficacy

Gonorrhea is a common sexually transmitted infection woridwide. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of complications such as pelvic inflammatory disease and infertility and increased likelihood of acquiring HIV infection. A better understanding of the innate immune response to this pathogen will lead to treatments that can lessen the infectious complications and support the development of protective vaccine strategies. We have developed two peptide mimics of conserved gonococcal lipooligosaccharide (LOS) derived oligosaccharides as potential experimental vaccine candidates. One, called 207, is displayed by 95% of gonococci in vivo; the second, called 2-1-L8, identifies an additional 3% of gonococci. Gonorrhea elicits an indiscriminate Th2 immune response in humans that results in antibodies that in the aggregate posses ill-defined function, resulting in failure of protective immunity against subsequent bouts of infection. 207 and 2-1-L8 antibodies and, in addition, antibodies against reduction modifiable protein (Rmp) are among the respondents to infection. Human 2C7 and 2-1-L8 antibodies exert complement (C) dependent killing; Rmp antibodies subvert (or block) C dependent killing and contribute to increased susceptibility to gonococcal infection. In Specific Aim 1, we hypothesize that a favorable ratio of 2C7+ 2-1-L8 antibodies H- Rmp antibodies is necessary to prevent infection after exposure. We will determine the ratio of 2C7+ 2-1-L8 antibodies ^ Rmp antibodies in the one-third of women who withstand infection after recent exposure. Gonococci bind directly to the human C regulators, 04 binding protein (C4BP), a classical C pathway regulator and Factor H, an alternative C pathway regulator, which interfere with numerous C dependent functions that kill gonococci. Specificity of C regulator binding is unique to humans; other animal species do not bind their own C regulators, which results in routine killing of gonococci by non-human C. In Specific Aim 2, we will adapt the mouse experimental model of gonococcal infection by testing the efficacy of 2C7 and 2-1-L8 peptide mimic vaccination in human transgenic mice that express human C4BP, factor H or both. We hypothesize that gonococcal infection will be enhanced in human C regulator transgenic mice, but that vaccine elicited immune antibodies, which overcome human regulator effects, will prevent or limit infection. In Specific Aim 3, we will refine the vaccine model further by including Rmp antibodies as part of the antibody repertoire in vaccinated mice to test susceptibility to gonococcal infection in these mice, thereby simulating the human condition where sufficient bactericidal antibody titers can overcome the blocking antibody effect.

淋病是世界范围内常见的性传播感染。女性通常很少或根本没有症状。 与感染有关，这往往会导致延误治疗和出现并发症 例如盆腔炎和不孕不育，以及感染艾滋病毒的可能性增加。一个 更好地了解对这种病原体的先天性免疫反应将导致治疗方法的减少 减少感染并发症，并支持制定保护性疫苗策略。我们有 开发了两种保守的淋球菌脂寡糖(LOS)来源的寡糖的多肽模拟物 作为潜在的实验疫苗候选者。一种名为207的淋球菌在体内95%的淋球菌中显示； 第二种，称为2-1-L8，可识别另外3%的淋球菌。淋病引起不加区别的Th2 人类的免疫反应，导致抗体在总体上具有不确定的功能， 导致对后续感染的保护性免疫失败。207和2-1-L8抗体 此外，针对还原可修饰蛋白(RMP)的抗体也属于 感染。人类2C7和2-1-L8抗体对补体(C)依赖的杀伤作用；RMP抗体 颠覆(或阻断)C依赖的杀伤，并有助于增加对淋球菌感染的易感性。在……里面 具体目标1，我们假设2C7+2-1-L8抗体H-RMP抗体的有利比例为 预防暴露后感染所必需的。我们将测定2C7+2-1-L8抗体和RMP的比例 在最近暴露后抵抗感染的女性中，有三分之一的人体内有抗体。淋球菌直接结合 对于人类的C调节因子，结合蛋白(C4BP)，一个经典的C途径调节因子，和一个 另一种C途径调节因子，干扰许多C依赖的功能，从而杀死淋球菌。 C调节因子结合的特异性是人类独有的；其他动物物种不结合它们自己的C 调节剂，导致非人类C的常规杀灭淋球菌。在特定目标2中，我们将适应 2C7和2-1-L8多肽对淋球菌感染小鼠实验模型的实验研究 在表达人C4BP和/或H因子的转基因小鼠中模拟疫苗接种。我们假设 在人类C调节基因转基因小鼠中，淋球菌感染将会增强，但该疫苗引发了 免疫抗体克服了人类调节器的影响，将预防或限制感染。以特定的目标 3，我们将进一步改进疫苗模型，将RMP抗体作为抗体库的一部分包含在 接种疫苗的小鼠，以测试这些小鼠对淋球菌感染的敏感性，从而模拟人类 足够的杀菌抗体效价可以克服封闭抗体效应的条件。