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.

淋病和衣原体是世界上最常见的细菌性性传播感染， 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，从而导致不孕或异位妊娠，它们增加了艾滋病毒的传播。 淋病和衣原体经常合并感染。淋球菌表现出了非凡的能力 对它遇到的每一种抗生素都有抗药性。淋病奈瑟菌（Ng） 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。我们的小组已经开发出一种淋球菌 包含Ng脂寡糖表位的肽模拟物（“模拟位”）的疫苗候选物，所述Ng脂寡糖表位 在体内由>95%的菌株表达。当该模拟位被配置为多抗原肽疫苗时， 降低小鼠阴道定殖模型中的Ng负荷。根据我们对 为了研究补体（C）抑制因子H（fH）与Ng的相互作用，我们融合了fH的A/g结合结构域， 与IgG Fc结合，产生一种新的免疫球蛋白，称为fH/Fc。一个点突变引入的fH片段， 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 on并杀死耐药细胞。 Ng.阐明促进Ng传播的因素并全面了解宿主 免疫应答对于开发针对Ng的安全有效的疫苗和治疗剂至关重要。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 目的1a我们将比较低与高传输的Ng逃避C，阳离子肽，并粘附于 并侵入人类子宫颈内细胞，以更好地了解为什么菌株在传播性上不同。正在进行 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， 预先存在的沙眼衣原体（Ct）感染增强了Ng从男性向女性的传播。在Aim中 1b我们将定义Cf载量和/或血清型在增加Ng传播中的作用。感染了Cf的小鼠 更大的Ng感染负担。感染Ng、Ct或双重Ng/Ct的小鼠的总体转录组分析 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; 将这些数据与人转录组数据（Genco，Project 4）进行比较。我们的模拟位Ng 将在目的2b中研究在小鼠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在感染单独耐药Ng和Ng/Ct共感染的小鼠中的功效。在Aim 3b 我们将使用缺乏关键C组分（C3、C5、C5 a受体）或吞噬作用的效应臂（例如， PMN、巨噬细胞或Fc受体），以阐明fH/Fc在体内的作用机制。