Starve and Kill: Engineered Antigens Targeting Nutrient Acquisition Pathways Essential for Gonococcal Infection and Disease

挨饿和杀死：针对淋球菌感染和疾病所必需的营养获取途径的工程抗原

• 批准号: 10355467
• 负责人: CYNTHIA N CORNELISSEN
• 金额: $ 180.61万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355467
• 关键词: Adjuvant; Animals; Antibiotics; Antibodies; Antigen Targeting; Antigenic Diversity; Antigens; Bacteria; Binding; Binding Proteins; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Communities; Community Outreach; Computer Models; Data; Detection; Development; Disease; Drug resistance; Economics; Engineering; Exhibits; Female genitalia; Formulation; Funding; Future; Genetic; Genomics; Goals; Gonorrhea; Growth; Heterogeneity; Human; Immune; Immune response; Immunity; Immunize; In Transferrin; Infection; Infection prevention; Iron; Life; Life Style; Ligand Binding; Ligands; Mediating; Membrane; Membrane Proteins; Metals; Misinformation; Modeling; Morbidity - disease rate; Names; Neisseria gonorrhoeae; Nutrient; Nutritional Immunity; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Prevalence; Process; Proteins; Public Health; Research; Resistance; Risk; Serum Proteins; Sexual Partners; Sexually Transmitted Agents; Sexually Transmitted Diseases; Site; Superbug; Surface; Surface Antigens; Symptoms; System; TFRC gene; Target Populations; Testing; Tissues; Trace metal; Transferrin; Vaccine Antigen; Vaccines; Virulent; Zinc; antimicrobial drug; base; clinically relevant; cross immunity; epidemiologic data; gonorrhea vaccine; human pathogen; human tissue; humanized mouse; immunogenic; implementation strategy; improved; innovation; international center; mathematical model; microbial; mouse model; mutant; novel; nutrient deprivation; pathogen; prevent; programs; receptor; reproductive tract; resistance factors; response; sex; success; translational research program; transmission process; trend; uptake; vaccine acceptance; vaccine development; vaccine discovery; vaccine formulation; vaccine hesitancy

Abstract/Summary Neisseria gonorrhoeae has re-emerged as a global public health concern as it causes roughly 100 million new infections each year and isolates have emerged that are resistant to all clinically-relevant antibiotics; these alarming trends have prompted the US Center for Disease Control to name N. gonorrhoeae as one of three `urgent' microbial threats. The success of N. gonorrhoeae is attributable in part to its capacity to colonize the female genital tract without obvious clinical manifestation, allowing it to persist undetected as it is spread to sexual partners. Consistent with this, N. gonorrhoeae does not express factors with overt virulent potential. Instead, it exhibits a lifestyle intent on avoiding and actively subverting immune detection, and expresses elegant systems to access highly restricted nutrient stores to support its growth within human tissues. This translational research program will exploit our recent success in targeting the receptor proteins that allow N. gonorrhoeae to acquire iron and zinc during infection; these trace metals are essential for life but effectively absent in mammalian tissues due to a process known as `nutritional immunity'. We have unexpectedly discovered that the bacterial surface-exposed receptor proteins that bind the host iron sequestering-serum protein transferrin does not elicit a protective immune response because it rapidly binds transferrin in the tissues, and that we can overcome this deficit by generating a point mutant that is structurally identical except that it does not bind transferrin. We will use this approach to generate immunogens that target alternative iron and zinc acquisition systems of N. gonorrhoeae, and then produce a multicomponent vaccine that elicits an immune response that will simultaneously starve the bacteria of these two essential nutrients and kill the bacteria through classical antibody-dependent activities. Along with this directly translational pursuit, we will also perform community outreach studies to understand the potential resistance to gonococcal vaccines among different stakeholder populations and reveal potential strategies to overcome these barriers. Then, our genomic and phenotypic analysis of the global diversity of the receptor systems that we are targeting will be integrated with global gonococcal epidemiology data and the understanding gained through our community-based studies to make informed predictions about the potential impact of different vaccine formulation and public health-focused implementation strategies on the global prevalence of N. gonorrhoeae. When complete, this program will therefore deliver a vaccine formulation that targets distinct but equally essential nutrient uptake pathways to confer sterilizing immunity against gonococcal infection and will provide actionable information that will guide the eventual implementation of this vaccine in a manner that will ultimately allow eradication of this devastating human-restricted pathogen.

摘要/摘要 Neisseria Gonorrhoeae已重新出现为全球公共卫生问题，因为它导致了大约1亿个新的新事物 每年出现感染和分离株，对所有与临床相关的抗生素具有抗性；这些 令人震惊的趋势促使美国疾病控制中心命名为N.淋病。 “紧急”微生物威胁。 N. gonorrhoeae的成功归因于其殖民的能力 女性生殖道没有明显的临床表现，使其在扩散到 性伴侣。与此相一致，淋病链球菌不会表达具有巨大潜力的因素。 相反，它表现出旨在避免和积极颠覆免疫检测的生活方式，并表达优雅 进入高度限制的养分店以支持其在人体组织中的生长的系统。这种翻译 研究计划将利用我们最近在靶向促使淋病的受体蛋白方面取得成功的成功 感染期间获得铁和锌；这些痕量金属对生命至关重要，但在哺乳动物中实际上没有 由于一种称为“营养免疫”的过程而引起的组织。我们意外地发现细菌 结合宿主铁隔离蛋白转移蛋白的表面暴露受体蛋白不会引起 保护性免疫反应是因为它迅速结合了组织中的转移蛋白，并且我们可以克服这一点 赤字通过产生一个在结构上相同的点突变体，除非它不结合转铁蛋白。我们将 使用这种方法生成靶向N的替代铁和锌采集系统的免疫原。 淋病，然后产生一种多组分疫苗，该疫苗会引起免疫反应 同时饿死了这两种必需营养素的细菌，并通过古典杀死细菌 抗体依赖性活性。除了这种直接翻译的追求外，我们还将表演社区 外展研究以了解不同利益相关者之间对淋球菌疫苗的潜在抵抗力 人群并揭示了克服这些障碍的潜在策略。然后，我们的基因组和表型 分析我们针对的受体系统的全球多样性将与全球集成 淋球菌流行病学数据以及通过我们的社区研究获得的理解，以使 关于不同疫苗配方和以公共卫生为中心的潜在影响的知情预测 有关淋病的全球患病率的实施策略。完成后，此程序将 因此，提供一种疫苗配方，该配方旨在针对不同但同样必不可少的营养摄取途径 赋予对淋球菌感染的免疫力进行灭菌，并将提供可行的信息，以指导 最终以最终允许消除这种毁灭性的方式实施该疫苗 人限制的病原体。