Molecular mechanism of streptococcal adaptation to host nutritional defenses

链球菌适应宿主营养防御的分子机制

• 批准号: 10559677
• 负责人: Muthiah Kumaraswami
• 金额: $ 40.38万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559677
• 关键词: Abscess; Active Immunization; Affinity; Anatomy; Antibodies; Antigenic Variation; Antigens; Autoimmune; Binding; Cell Wall; Cell membrane; Cells; Cessation of life; Child; Coated vesicle; Data; Development; Disease; Engineering; Environment; Face; Genetic Variation; Gram-Positive Bacteria; Growth; Healthcare; Heart Diseases; Human; Immune; Immune response; Immunization; Infection; Integration Host Factors; Leukocyte L1 Antigen Complex; Licensing; Masks; Mediating; Membrane; Metals; Mission; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Nutritional; Oropharyngeal; Pathogenesis; Peptidoglycan; Persons; Pharyngeal structure; Pharyngitis; Proteins; Public Health; Research; Resistance; Rheumatic Heart Disease; Role; Safety; Serotyping; Site; Starvation; Streptococcal Infections; Streptococcal Vaccines; Streptococcus; Streptococcus pyogenes; Stress; Surface; System; Testing; Thick; Translational Research; United States National Institutes of Health; Vaccination; Vaccines; Vesicle; Virulence; Work; Zinc; cell capsule; cross reactivity; disorder prevention; extracellular; human pathogen; human tissue; immunogenic; immunogenicity; interdisciplinary approach; metal chelator; microbial; mortality; neutrophil; nonhuman primate; novel; novel vaccines; nutrient deprivation; pathogen; prevent; prophylactic; protective efficacy; recruit; side effect; uptake; vaccination strategy; vaccine candidate; vaccine development; Abscess; Active Immunization; Affinity; Anatomy; Antibodies; Antigenic Variation; Antigens; Autoimmune; Binding; Cell Wall; Cell membrane; Cells; Cessation of life; Child; Coated vesicle; Data; Development; Disease; Engineering; Environment; Face; Genetic Variation; Gram-Positive Bacteria; Growth; Healthcare; Heart Diseases; Human; Immune; Immune response; Immunization; Infection; Integration Host Factors; Leukocyte L1 Antigen Complex; Licensing; Masks; Mediating; Membrane; Metals; Mission; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Nutritional; Oropharyngeal; Pathogenesis; Peptidoglycan; Persons; Pharyngeal structure; Pharyngitis; Proteins; Public Health; Research; Resistance; Rheumatic Heart Disease; Role; Safety; Serotyping; Site; Starvation; Streptococcal Infections; Streptococcal Vaccines; Streptococcus; Streptococcus pyogenes; Stress; Surface; System; Testing; Thick; Translational Research; United States National Institutes of Health; Vaccination; Vaccines; Vesicle; Virulence; Work; Zinc; cell capsule; cross reactivity; disorder prevention; extracellular; human pathogen; human tissue; immunogenic; immunogenicity; interdisciplinary approach; metal chelator; microbial; mortality; neutrophil; nonhuman primate; novel; novel vaccines; nutrient deprivation; pathogen; prevent; prophylactic; protective efficacy; recruit; side effect; uptake; vaccination strategy; vaccine candidate; vaccine development

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.

链球菌为链球菌，也称为A组链球菌（气），是主要的人类病原体 这会导致明显的发病率和死亡率。气体感染会导致几种疾病 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，至少有3400万人患有RHD的人每年造成345,000人死亡。因此， 人类天然气疫苗的开发仍然是医疗保健的重点。但是，广泛的保护性 由于候选疫苗的抗原差异，有执照的气体疫苗仍然难以捉摸 不同的气体血清型，病原体的遗传多样性以及抗体的交叉反应性 与人体组织的气体抗原。克服这些挑战并保护公共卫生免受天然气 疾病，至关重要的是确定新颖的疫苗靶标和/或制定新的疫苗接种策略 对气体疾病产生广泛有效的保护。我们最近的研究表明 高度保守的细菌金属采集系统是关键的毒力决定因素，并且 有效的疫苗靶标能够赋予针对气体疾病的跨色谱保护。这 金属进口商与宿主营养免疫机制竞争，在感染过程中获取金属 并促进敌对宿主环境中的细菌生存。宿主部署营养免疫 作为先天免疫的组成部分，通过营养剥夺延迟微生物的生长。 气体感染的脓肿富含宿主因子，钙骨蛋白（CP），该因子隔离了Zn 定植表面限制气体生长。但是，气体承受CP的猛烈攻击并成功 通过使用高亲和力Zn进口商ADCABC来复制主机。该模型的主要警告 是，在气体和其他革兰氏阳性细菌中，细胞膜结合的ADCABC样进口商是 埋在厚的细胞壁层下方。 ADCABC的蒙版亚细胞定位未能 解释其作为有效宿主营养防御的竞争性ZN吸收机制的功能 及其作为疫苗靶标的功效。该提议的主要目的是确定 气体使用ADCA逃避宿主营养防御的机制，并评估新颖的ADCA- 基于其针对人类气体感染的保护性疗效的基于疫苗接种策略。使用 多学科方法，我们将检验该提案的中心假设，即气体使用非 - 复制无细胞的膜囊泡（MV），用ADCABC涂有Zn采集并颠覆CP- 介导的Zn限制。在拟议的研究完成时，MV介导的机械基础 燃气锌的采集将被描述并基于蛋白质和MV的ADCA的保护性效力 将评估预防天然气疾病的疫苗接种。