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， 对妇女的生殖健康产生不利影响。除了盆腔炎等并发症 疾病和输卵管疤痕导致不孕症或异位妊娠，它们会增加艾滋病毒的传播。 淋病和衣原体经常以混合感染的形式存在。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 对第三代头孢菌素具有抗药性的菌株预示着一个无法治愈的淋病时代的到来。 目前迫切需要针对Ng的疫苗和新的治疗方法。我们小组已经研制出一种淋球菌 候选疫苗，包含Ng脂低聚糖表位的模拟多肽(模拟表位) 95%的菌株在体内表达。当这种模拟表位被配置为多抗原肽疫苗时， 降低小鼠阴道定植模型中的Ng负荷。根据我们的工作知识， 补体(C)抑制因子H(Fh)与Ng的相互作用，我们融合了Fh的A/g结合域 将其与免疫球蛋白Fc结合，形成一种新型的免疫治疗药物，称为Fh/Fc。猪瘟病毒Fh片段中引入的一个点突变 Fh/Fc阻断了C‘介导的宿主细胞裂解，但允许Fh/Fc结合、激活C-On和杀伤耐药 Ng.阐明促进Ng传播的因素并获得对宿主的全球了解 对于开发安全有效的Ng疫苗和疗法来说，应答是至关重要的。这些研究 在衣原体联合感染的背景下高度相关，这是一种常见的临床情况，因为 衣原体可能会破坏免疫，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菌株的传播效率远远低于其他密切相关的Ng谱系。在……里面 目标1a我们将比较低透射率和高透过率的Ng逃避C，阳离子多肽的能力，并粘着 并入侵人类宫颈内细胞，以更好地了解为什么菌株的传播性不同。正在进行中 南京中国性病门诊现场Ng感染者及其女性伴侣的数据分析表明， 先前存在的沙眼衣原体(Ct)感染增强了Ng从男性向女性的传播。在AIM 1B我们将确定Cf负载和/或血清变量在增加Ng传播中的作用。感染CFs的小鼠遭受 Ng感染的负担更大。Ng、Ct和双重Ng/Ct感染小鼠的整体转录组分析 在AIM 2a中将进行混合感染，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，Project 4)进行比较。我们的模拟表位Ng的能力 在Aim 2b中，将研究在小鼠A/g/CF混合感染模型中减毒Ng的候选疫苗。Aim 3a意志 评价Fh/Fc对耐药Ng和Ng/Ct混合感染小鼠的疗效。在目标3b中 我们将使用缺乏关键C成分(C3、C5、C5a受体)或吞噬效应臂的小鼠(例如， 中性粒细胞、巨噬细胞或Fc受体)，阐明Fh/Fc在体内的作用机制。