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: 7764293
• 负责人: Peter A. Rice
• 金额: $ 29.14万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764293
• 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; Neisseria gonorrhoeae; Oligosaccharides; Pathway interactions; Pelvic Inflammatory Disease; Peptides; Predisposition; Protein C; Proteins; Resistance to infection; Respondent; Role; Sexual Partners; Sexually Transmitted Diseases; Simulate; Site; Specificity; Symptoms; System; Testing; Transgenic Mice; Urethra; Vaccinated; Vaccination; Vaccines; Woman; 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; 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; Neisseria gonorrhoeae; Oligosaccharides; Pathway interactions; Pelvic Inflammatory Disease; Peptides; Predisposition; Protein C; Proteins; Resistance to infection; Respondent; Role; Sexual Partners; Sexually Transmitted Diseases; Simulate; Site; Specificity; Symptoms; System; Testing; Transgenic Mice; Urethra; Vaccinated; Vaccination; Vaccines; Woman; 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.

淋病是一种常见的性传播感染。妇女通常很少或没有症状 与感染相关，这通常会导致治疗延迟和并发症的发展 例如骨盆炎症性疾病和不育以及增加HIV感染的可能性增加。一个 更好地理解对这种病原体的先天免疫反应将导致可以减少的治疗 感染并发症并支持保护性疫苗策略的发展。我们有 开发了两个肽模仿的循环酸球菌（LOS）衍生的寡糖 作为潜在的实验疫苗候选物。一个称为207的人，由95％的淋球菌在体内显示；这 其次称为2-1-L8，鉴定出淋球菌的3％。淋病引起不加区分的TH2 人类中的免疫反应导致抗体，这些抗体在骨料中具有不确定的功能， 导致保护性免疫力失败，以抵抗随后的感染爆发。 207和2-1-L8抗体 此外，抗还原可修改蛋白（RMP）的抗体是受访者 感染。人2C7和2-1-L8抗体作用补体（C）依赖性杀戮； RMP抗体 颠覆（或阻滞）依赖性杀戮，并导致对淋球菌感染的敏感性增加。在 具体目的1，我们假设2C7+ 2-1-1-L8抗体H- RMP抗体的有利比率为 暴露后防止感染所必需的。我们将确定2C7+ 2-1-L8抗体的比率 ^ rmp 在最近暴露后承受感染的三分之一女性的抗体。淋球菌直接结合 对于人C调节剂，04结合蛋白（C4BP），经典的C途径调节剂和因子H，A 替代C途径调节剂，会干扰杀死淋球菌的许多依赖性功能。 C调节剂结合的特异性是人类独有的。其他动物不结合自己的c 调节器，导致非人类C常规杀死淋球菌。在特定的目标2中，我们将适应 通过测试2C7和2-1-L8肽的淋球菌感染的小鼠实验模型 表达人C4bp，因子H或两者的人类转基因小鼠中的模拟疫苗接种。我们假设 人类C调节剂转基因小鼠将增强淋球菌感染，但该疫苗引起 克服人类调节剂效应的免疫抗体将预防或限制感染。在特定目标中 3，我们将通过将RMP抗体作为抗体库的一部分，进一步完善疫苗模型 接种疫苗的小鼠以测试这些小鼠对淋球菌感染的易感性，从而模拟了人类 足够的杀菌抗体滴度可以克服阻断抗体效应的条件。