Experimental and human protective immunity to Neisseria gonorrhoeae

淋病是一种常见的性传播疾病。女性通常很少或没有症状 与感染有关，这往往导致治疗延误和并发症的发展 如盆腔炎和不孕症，以及增加感染艾滋病毒的可能性。一 更好地了解这种病原体的先天免疫反应将导致治疗， 感染并发症，并支持保护性疫苗战略的发展。我们有 开发了两种保守的淋球菌脂寡糖（LOS）衍生寡糖的肽模拟物 作为潜在的实验性疫苗候选者。一种称为207，在体内95%的淋球菌中显示; 第二种称为2-1-L 8，鉴定出另外3%的淋球菌。淋病可分泌不加选择的Th 2 在人体内产生抗体的免疫反应， 导致对随后的感染的保护性免疫失败。207和2-1-L 8抗体 此外，针对还原修饰蛋白（Rmp）的抗体也在受访者中， 感染人2C 7和2-1-L 8抗体发挥补体（C）依赖性杀伤; 破坏（或阻断）C依赖性杀伤并有助于增加对淋球菌感染的易感性。在 具体目标1，我们假设2C 7 + 2-1-L 8抗体H-Rmp抗体的有利比例是 以防止感染后暴露。我们将确定2C 7 + 2-1-L 8抗体的比率 三分之一的妇女在最近接触过感染后能够抵抗感染。淋球菌直接结合 对于人C调节因子，04结合蛋白（C4 BP），一种经典的C途径调节因子和H因子， 替代C途径调节剂，其干扰杀死淋球菌的许多C依赖性功能。 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，其导致非人C.在具体目标2中，我们将适应 通过测试2C 7和2-1-L 8肽对淋球菌感染小鼠实验模型的功效 在表达人C4 BP、因子H或两者的人转基因小鼠中模拟疫苗接种。我们假设 淋球菌感染将在人C调节因子转基因小鼠中增强，但疫苗引起 免疫抗体克服了人类调节剂的作用，将预防或限制感染。具体目标 3，我们将进一步完善疫苗模型，包括Rmp抗体作为抗体库的一部分， 接种疫苗的小鼠，以测试这些小鼠对淋球菌感染的易感性，从而模拟人类 足够的杀菌抗体滴度可以克服封闭抗体效应的条件。

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.