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

摘要/摘要 淋球菌重新成为全球公共卫生问题，因为它导致大约1亿新的 每年都会出现对所有临床相关抗生素都具有抗药性的感染和分离株；这些 令人震惊的趋势促使美国疾病控制中心将淋病奈瑟菌列为 “紧急”的微生物威胁。淋病奈瑟氏菌的成功部分归因于其在 没有明显临床表现的女性生殖道，使其在传播到 性伴侣。与此一致的是，淋球菌不表达具有明显毒力潜力的因子。 相反，它展示了一种旨在避免和积极颠覆免疫检测的生活方式，并表达了优雅的 系统访问高度受限的营养储存，以支持其在人体组织内的生长。此翻译 研究计划将利用我们最近在靶向受体蛋白方面的成功，使淋病奈瑟菌能够 在感染期间获得铁和锌；这些微量金属是生命所必需的，但在哺乳动物中实际上是不存在的 由于一种被称为‘营养免疫’的过程而产生的组织。我们出人意料地发现细菌 与宿主铁隔离结合的表面暴露的受体蛋白-血清蛋白转铁蛋白不能诱导 一种保护性免疫反应，因为它能迅速结合组织中的转铁蛋白，而我们可以克服这一点 缺陷是产生一个结构上相同的点突变，除了它不结合转铁蛋白。我们会 使用这种方法产生针对N。的替代铁和锌获取系统的免疫原。 然后生产一种多组分疫苗，引起免疫反应，从而 同时使细菌缺乏这两种必需的营养物质，并通过经典的 抗体依赖的活动。伴随着这种直接的翻译追求，我们也将表演社区 外展研究以了解不同利益相关者对淋球菌疫苗的潜在耐药性 并揭示了克服这些障碍的潜在战略。然后，我们的基因组和表型 对我们目标的受体系统的全球多样性的分析将与全球 淋病流行病学数据和我们通过社区研究获得的理解，以使 对不同疫苗配方和关注公共卫生的潜在影响的知情预测 关于淋病全球流行的实施战略。完成后，该计划将 因此，提供一种针对不同但同样重要的营养吸收途径的疫苗配方，以 提供对淋球菌感染的灭菌免疫力，并将提供可操作的信息，以指导 最终实施这种疫苗的方式将最终消除这种毁灭性的 人类限制的病原体。

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.