Vaccines and Immunotherapeutics against gonorrhea in the contex of Chlamydia co

衣原体背景下的淋病疫苗和免疫治疗

• 批准号: 9118063
• 负责人: SANJAY RAM
• 金额: $ 49.86万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118063
• 关键词: Affect; Animals; Antibiotics; Antigens; Attenuated; Bacteriolysis; Basic Science; Binding; Binding Proteins; C5a anaphylatoxin receptor; Ceftriaxone; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Characteristics; Chimeric Proteins; China; Chlamydia; Chlamydia trachomatis; Cicatrix; Clinic; Clinical; Complement; Complement Factor H; Complement Inactivators; Cytolysis; Data; Data Analyses; Deposition; Development; Disease; Disease Outcome; Drug-resistant Neisseria Gonorrhoeae; Ectopic Pregnancy; Epidemiology; Epitopes; Fc Receptor; Female; Generations; Genes; Gonorrhea; HIV; Host Defense; Human; Immune; Immune response; Immunity; Immunoglobulin G; Immunotherapeutic agent; In Vitro; Individual; Infection; Infertility; Invaded; Knowledge; Lead; Light; Link; Mediating; Microbe; Modeling; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Organism; Pathogenicity; Pelvic Inflammatory Disease; Peptide Vaccines; Peptides; Phagocytes; Phagocytosis; Play; Point Mutation; Population; Public Health; Reproductive Health; Resistance; Role; Sexually Transmitted Diseases; Site; Specimen; Superbug; Testing; Time; Tissue Model; Translational Research; VDAC1 gene; Vaccines; Vagina; Woman; Work; age group; arm; base; chronic pelvic pain; clinical practice; co-infection; cytokine; design; disorder prevention; epidemiologic data; genome-wide; gonorrhea vaccine; in vivo; inhibitor/antagonist; inner city; interest; killings; lipooligosaccharide; macrophage; male; men; mouse model; novel; novel therapeutics; novel vaccines; pathogen; peptidomimetics; receptor; reproductive tract; resistant strain; socioeconomics; statistics; therapeutic vaccine; transcriptome; transcriptome sequencing; transmission process; vaccine candidate

Gonorrhea and chlamydia are the most common bacterial sexually transmitted infections worldwide and adversely impact the reproductive health of women. In addition to complications such as pelvic inflammatory disease and tubal scarring with consequent infertility or ectopic pregnancy, they enhance HIV transmission. Gonorrhea and chlamydia frequently exist as coinfections. The gonococcus has displayed a remarkable ability to become resistant to every antibiotic that it has encountered. The emergence of Neisseria gonorrhoeae (Ng) strains that are resistant to third-generation cephalosporins has heralded an era of untreatable gonorrhea. Vaccines and novel therapeutics against Ng are needed urgently. Our group has developed a gonococcal vaccine candidate that comprises a peptide mimic (a 'mimitope') of a Ng lipooligosaccharide epitope that is expressed by >95% of strains in vivo. This mimitope, when configured as a multi-antigen peptide vaccine, decreases Ng burden in the mouse vaginal colonization model. Based on our working knowledge of interactions of the complement (C) inhibitor factor H (fH) with Ng, we have fused the A/g-binding domains of fH to IgG Fc to create a novel immunotherapeutic, called fH/Fc. A point mutation introduced in the fH fragment of fH/Fc abrogated C'-mediated lysis of host cells, yet allowed fH/Fc to bind to, activate C on and kill drug-resistant Ng. Elucidating factors that facilitate Ng transmission and gaining a global understanding of host responses are critical for developing safe and effective vaccines and therapeutics against Ng. These studies are highly relevant in context of chlamydia coinfection, a commonly encountered clinical scenario, because chlamydia may subvert immunity to increase Ng burden that our vaccine and fH/Fc must overcome. We have observed that certain Ng strains are transmitted far less efficiently than other closely related Ng lineages. In Aim 1a we will compare the ability of low vs. high transmitted Ng to evade C, cationic peptides, and adhere to and invade human endocervical cells to better understand why strains differ in their transmissibility. Ongoing data analysis of Ng infected men and their female partners at the Nanjing, China, STD clinic site suggest that preexisting Chlamydia trachomatis (Ct) infection enhances the transmission of Ng from men to women. In Aim 1b we will define the role of Cf load and/or serovar in increasing Ng transmission. Mice infected with Cf suffer a greater burden of Ng infection. Global transcriptome analyses on mice infected with Ng, Ct or dual Ng/Ct coinfection will be performed in Aim 2a to elucidate how Cf subverts host defenses to enhance Ng infection; these data will be compared with human transcriptome data (Genco, Project 4). The ability of our mimitope Ng vaccine candidate to attenuate Ng in the mouse A/g/Cf coinfection model will be studied in Aim 2b. Aim 3a will evaluate the efficacy of fH/Fc in mice infected with drug-resistant Ng alone and Ng/Ct coinfection. In Aim 3b we will use mice that lack critical C components (C3, C5, C5a receptor) or effector arms of phagocytosis (e.g., PMNs, macrophages or Fc receptors) to elucidate the mechanism of action of fH/Fc in vivo.

淋病和衣原体是全世界最常见的细菌性传播感染， 对女性的生殖健康造成不良影响。除了盆腔炎等并发症外 疾病和输卵管疤痕以及随之而来的不孕或宫外孕，它们会增强艾滋病毒的传播。 淋病和衣原体经常作为合并感染存在。淋球菌表现出了非凡的能力 对它遇到的每一种抗生素都产生抗药性。淋病奈瑟菌 (Ng) 的出现 对第三代头孢菌素耐药的菌株预示着淋病无法治愈的时代的到来。 迫切需要针对 Ng 的疫苗和新疗法。我们课题组开发了淋球菌 包含 Ng 脂寡糖表位的肽模拟物（“模拟表位”）的候选疫苗 体内>95%的菌株表达。当该模拟表位配置为多抗原肽疫苗时， 减少小鼠阴道定植模型中的 Ng 负担。根据我们的工作知识 补体 (C) 抑制剂因子 H (fH) 与 Ng 的相互作用，我们融合了 fH 的 A/g 结合域 IgG Fc 来创造一种新型免疫疗法，称为 fH/Fc。 fH 片段中引入的点突变 fH/Fc 消除了 C' 介导的宿主细胞裂解，但允许 fH/Fc 结合、激活 C 并杀死耐药细胞 吴。阐明促进 Ng 传播的因素并获得对宿主的全球了解 应对措施对于开发针对 Ng 的安全有效的疫苗和疗法至关重要。这些研究 与衣原体合并感染（一种常见的临床情况）高度相关，因为 衣原体可能会破坏免疫力，增加我们的疫苗和 fH/Fc 必须克服的 Ng 负担。我们有 观察到某些 Ng 菌株的传播效率远低于其他密切相关的 Ng 谱系。在 目标 1a 我们将比较低传输 Ng 与高传输 Ng 逃避 C、阳离子肽和粘附的能力 并侵入人类宫颈内细胞，以更好地了解为什么菌株的传播能力不同。进行中 对中国南京性病诊所的 Ng 感染男性及其女性伴侣的数据分析表明 先前存在的沙眼衣原体 (Ct) 感染会增强 Ng 从男性向女性的传播。瞄准 在图 1b 中，我们将定义 Cf 负载和/或血清变量在增加 Ng 传输中的作用。感染 Cf 的小鼠遭受痛苦 Ng感染负担更大。对感染 Ng、Ct 或双重 Ng/Ct 的小鼠进行全局转录组分析 目标 2a 中将进行共感染，以阐明 Cf 如何破坏宿主防御以增强 Ng 感染； 这些数据将与人类转录组数据进行比较（Genco，项目 4）。我们的模拟表位 Ng 的能力 目标 2b 将研究在小鼠 A/g/Cf 共感染模型中减弱 Ng 的候选疫苗。目标 3a 将 评估 fH/Fc 对单独感染耐药 Ng 和 Ng/Ct 共感染的小鼠的疗效。瞄准 3b 我们将使用缺乏关键 C 成分（C3、C5、C5a 受体）或吞噬作用效应臂（例如， PMN、巨噬细胞或 Fc 受体）阐明 fH/Fc 在体内的作用机制。