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: 9331418
• 负责人: SANJAY RAM
• 金额: $ 49.82万
• 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/9331418
• 关键词: Affect; Animals; Antibiotics; Antigens; Attenuated; Bacteriolysis; Basic Science; Binding; Binding Proteins; C5a anaphylatoxin receptor; Cations; 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; GTP-Binding Protein alpha Subunits, Gs; 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 Agents; Sexually Transmitted Diseases; Site; Specimen; Superbug; Testing; Therapeutic; Time; Tissue Model; Translational Research; Tube; VDAC1 gene; Vaccines; Vagina; Woman; Women' s Health; age group; arm; base; chronic pelvic pain; clinical practice; co-infection; complement C3 precursor; cytokine; design; disorder prevention; epidemiologic data; genome-wide; in vivo; inner city; killings; lipooligosaccharide; macrophage; male; men; mouse model; novel; novel therapeutics; novel vaccines; pathogen; peptidomimetics; receptor; reproductive tract; resistant strain; socioeconomic disadvantage; statistics; 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.

淋病和衣原体是全球最常见的细菌性传播感染， 不利影响妇女的生殖健康。除了并发症，例如骨盆炎症 疾病和输卵管疤痕，导致不孕或异位妊娠，它们增强了HIV的传播。 淋病和衣原体经常以共同感染而存在。淋球菌表现出了非凡的能力 对遇到的每种抗生素具有抵抗力。 Neisseria Gonorrhoeae（NG）的出现 对第三代头孢菌素具有抵抗力的菌株预示着一个无法治疗的淋病时代。 迫切需要疫苗和针对NG的新型治疗剂。我们的小组已经发展了一个淋球菌 包括脂肪含糖表位的肽模仿肽（a'Mimitope）的疫苗候选者 由> 95％的体内菌株表达。此模拟物在配置为多抗原肽疫苗时， 减轻小鼠阴道定植模型中的NG负担。基于我们对 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 到IgG FC创建一种新型的免疫治疗性，称为FH/FC。在FH片段中引入的点突变 FH/FC废除了宿主细胞的C'M介导的裂解，但允许FH/FC结合，激活C并杀死抗药性 ng。阐明促进NG传播并获得对宿主的全球理解的因素 反应对于开发安全有效的疫苗和针对NG的治疗剂至关重要。这些研究 在衣原体共感染的背景下，通常遇到的临床情况很重要，因为 衣原体可能会颠覆免疫力，以增加我们的疫苗和FH/FC必须克服的NG负担。我们有 观察到某些NG菌株的传输效率要比其他密切相关的NG谱系少得多。在 目的1a我们将比较低传播NG逃避C，阳离子肽的能力，并遵守 并入侵人类宫颈细胞，以更好地了解为什么菌株的可传播性有所不同。正在进行 中国南京的NG男性及其女性伴侣的数据分析表明， 先前存在的衣原体沙眼（CT）感染增强了NG从男性到女性的传播。目标 1b我们将定义CF负载和/或血清在增加NG传输中的作用。感染CF受苦的小鼠 NG感染负担更大。对感染NG，CT或Dual NG/CT的小鼠的全局转录组分析 将在AIM 2A中进行共感染，以阐明CF如何颠覆宿主防御以增强NG感染； 这些数据将与人类转录组数据（Genco，项目4）进行比较。我们的模拟物NG的能力 将在AIM 2B中研究候选疫苗以减弱小鼠A/G/CF共感染模型的NG。 AIM 3A会 评估FH/FC在仅感染药物NG和NG/CT共感染的小鼠中的功效。在AIM 3B中 我们将使用缺乏关键C成分（C3，C5，C5A受体）或吞噬作用臂的小鼠（例如 PMN，巨噬细胞或FC受体）阐明了体内FH/FC的作用机理。