Molecular mechanism of streptococcal adaptation to host nutritional defenses

化脓性链球菌，又称A组链球菌(GAS)，是人类的主要致病菌 这会导致严重的发病率和死亡率。气体感染可导致多种疾病 包括风湿性心脏病(RHD)，这是儿童获得性心脏病的主要原因。 在全球范围内，每年至少有3400万风湿性心脏病患者导致34.5万人死亡。因此， 人类气体疫苗的开发仍然是医疗保健的优先事项。然而，一个广泛的保护性 由于候选疫苗的抗原性不同，获得许可的GAS疫苗仍然难以获得 不同的GAS血清型、病原体的遗传多样性以及抗体的交叉反应 人体组织中的气体抗原。克服这些挑战，保护公众健康免受毒气危害 对于疾病，至关重要的是确定新的疫苗目标和/或制定新的疫苗接种战略， 对气体疾病产生广泛和有效的保护。我们最近的研究表明 高度保守的细菌金属获取系统是关键的毒力决定因素和 有效的疫苗靶点能够提供针对气体疾病的交叉血清型保护。这个 金属进口商在感染期间与宿主的营养免疫机制竞争以获得金属 并促进细菌在恶劣的寄主环境中生存。宿主部署营养免疫 作为先天免疫的组成部分，通过营养剥夺来抑制微生物生长的机制。 气体感染的脓肿富含宿主因子钙保护素(CP)，它将锌从脓肿中隔离出来。 殖民表面，以限制气体的增长。然而，GAS成功地经受住了CP的冲击 通过利用高亲和力的锌导入蛋白AdcABC在宿主中复制。对此模型有一个主要的警告 在GAS和其他革兰氏阳性细菌中，细胞膜结合的AdcABC样导入子是 埋在厚厚的细胞壁层下面。AdcABC的掩蔽亚细胞定位未能 解释它作为竞争的锌吸收机制对抗有效的寄主营养防御的功能 以及它作为疫苗靶标的有效性。这项建议的主要目标是确定 GAS利用ADCA逃避宿主营养防御的机制，并评价新的ADCA- 基于疫苗接种策略，以防止类似人的气体感染的保护效果。使用 多学科的方法，我们将测试这一提议的中心假设，即气体使用非 复制的无细胞膜泡(MV)包被AdcABC用于锌的获取和颠覆CP- 中介锌限制。在拟议的研究完成后，MV介导的机制基础 以蛋白质和MV为基础的ADCA将描述气体锌的获取和保护效果 将对预防气体疾病的疫苗接种进行评估。

Streptococcus pyogenes, also known as group A streptococcus (GAS), is a major human pathogen that causes significant morbidity and mortality. GAS infections can lead to several disease conditions including rheumatic heart disease (RHD), the major cause of acquired heart disease in children. Globally, at least 34 million people living with RHD causing 345,000 deaths per year. Thus, the development of a human GAS vaccine remains a healthcare priority. However, a broadly protective licensed GAS vaccine remains elusive due to the antigenic variation in vaccine candidates among different GAS serotypes, genetic diversity of the pathogen, and cross-reactivity of antibodies against GAS antigens with human tissues. To overcome these challenges and protect public health from GAS diseases, it is critical to identify novel vaccine targets and/or develop new vaccination strategies that produce broad and effective protection against GAS diseases. Our recent studies demonstrated that the highly conserved bacterial metal acquisition systems are critical virulence determinants and effective vaccine targets capable of conferring cross-serotypic protection against GAS diseases. The metal importers compete with host nutritional immune mechanisms to acquire metals during infection and promote bacterial survival in hostile host environments. Host deploys nutritional immune mechanisms, as components of innate immunity, to retard microbial growth by nutrient deprivation. GAS infected abscesses are enriched with host factor, calprotectin (CP), which sequesters Zn from the colonization surfaces to limit GAS growth. However, GAS withstands CP onslaught and successfully replicates in the host by employing the high-affinity Zn importer, AdcABC. A major caveat to this model is that, in GAS and other gram-positive bacteria, the cell membrane-bound AdcABC-like importers are buried underneath the thick cell wall layer. The masked subcellular localization of AdcABC fails to explain its function as a competitive Zn uptake mechanism against the efficient host nutritional defenses and its efficacy as a vaccine target. The primary objective of this proposal is to determine the mechanisms by which GAS uses AdcA to evade host nutritional defenses, and evaluate novel AdcA- based vaccination strategies for its protective efficacy against human-like GAS infections. Using a multidisciplinary approach, we will test the central hypothesis of this proposal that GAS uses non- replicating, cell-free membrane vesicles (MV) coated with AdcABC for Zn acquisition and subverts CP- mediated Zn limitation. At the completion of the proposed study, the mechanistic basis for MV-mediated GAS Zn acquisition will be delineated and protective efficacy of protein- and MV-based AdcA vaccination for GAS disease prevention will be assessed.