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

摘要/概要 淋病奈瑟菌已重新成为全球公共卫生问题，因为它导致大约1亿新的 感染每年和隔离出现耐药的所有临床相关的抗生素;这些 令人担忧的趋势促使美国疾病控制中心将N.淋病作为三种 “紧急”微生物威胁。N的成功淋病的部分原因是它的能力，殖民 女性生殖道没有明显的临床表现，使其在传播到 性伴侣与此同时，N。淋病不表达具有明显毒力潜力的因子。 相反，它展示了一种生活方式，旨在避免和积极颠覆免疫检测，并表达了优雅 系统访问高度限制的营养储存，以支持其在人体组织内的生长。这种平移 研究计划将利用我们最近在靶向受体蛋白方面的成功，淋球菌对 在感染过程中获得铁和锌;这些微量金属是生命所必需的，但在哺乳动物中有效缺乏 这是由于一个被称为“营养免疫”的过程。我们意外地发现， 结合宿主铁螯合血清蛋白转铁蛋白的表面暴露的受体蛋白不引起 一种保护性的免疫反应，因为它能迅速结合组织中的转铁蛋白，我们可以克服这一点， 通过产生除了不结合转铁蛋白之外结构上相同的点突变体来产生缺陷。我们将 使用这种方法来产生针对N. 淋病，然后生产一种多组分疫苗，激发免疫反应， 同时使细菌缺乏这两种必需营养素，并通过经典的 抗体依赖性活性。沿着这种直接的翻译追求，我们还将执行社区 开展外联研究，了解不同利益攸关方对淋球菌疫苗的潜在耐药性 并揭示克服这些障碍的潜在战略。然后，我们的基因组和表型 对我们所针对的受体系统的全球多样性的分析将与全球 淋球菌流行病学数据和通过我们以社区为基础的研究获得的理解， 对不同疫苗配方的潜在影响作出知情预测， 实施战略的全球流行N.淋病完成后，该计划将 因此，提供了一种疫苗制剂，其靶向不同但同样重要的营养摄取途径， 赋予对淋球菌感染的杀菌免疫力，并将提供指导 最终实施这种疫苗的方式，最终将允许根除这种毁灭性的 人类特有的病原体

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.