Development of an alpha-1 phosphate mannan vaccine against the emerging fungal pathogen Candida auris.

开发针对新兴真菌病原体耳念珠菌的 α-1 磷酸甘露聚糖疫苗。

• 批准号: 10573467
• 负责人: David L. Williams
• 金额: $ 22.5万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573467
• 关键词: Acids; Address; Adjuvant; Antifungal Agents; Antifungal Therapy; Awareness; B-Lymphocytes; Candida; Candida albicans; Candida auris; Candidiasis; Carbohydrates; Cell surface; Clinical; Dangerousness; Data; Decontamination; Development; Disease Outbreaks; Dose; Drug resistance; Emerging Communicable Diseases; Environment; Exhibits; Fluconazole resistance; Formulation; Foundations; Fungal Drug Resistance; Future; Genetic Transcription; Goals; Health Personnel; Healthcare; Hospitals; Immune; Immune response; Immunity; Immunologics; Infection; Innate Immune Response; Literature; Mannans; Morbidity - disease rate; Mus; Nursing Homes; Patients; Persons; Phagocytes; Phenotype; Prevention; Protocols documentation; Public Health; Reagent; Reporting; Research; Resistance; Side; Skin; Skin colonization; Structure; Surface; T-Lymphocyte; Time; Vaccination; Vaccines; adaptive immune response; draining lymph node; efficacy evaluation; immunological status; inorganic phosphate; mortality; mouse model; novel; organ injury; pathogen; pathogenic fungus; prevent; prototype; resistant strain; response; sugar; transmission process; vaccine development; vaccine efficacy; vaccine formulation; virtual

Candida auris is a fungal pathogen that has been identified as an emerging infectious disease and a public health threat. C. auris is notable for its resistance to antifungal therapy, its transmissibility, its high mortality rate as well as its ability to colonize patients, healthcare personnel and healthcare environments. C. auris strains are typically resistant to fluconazole and approximately half of C. auris strains are resistant to two or more anti-fungal drugs. C. auris causes nosocomial outbreaks of invasive candidiasis with mortality rates of ~60%. There are five distinct clades of C. auris, all of which appear to have evolved since 1996. In addition to its drug resistance, C. auris can colonize skin, spread from person-to-person and survive in healthcare environments for long periods of time. These features are unique to C. auris. C. auris is resistant to many standard decontamination reagents and protocols, which has resulted in the rapid spread of this pathogen throughout the world. This makes it a particularly dangerous emerging fungal pathogen. Thus, it is not surprising that C. auris is the first fungal pathogen that has been identified as a public health threat. What is needed is a C. auris specific vaccine that can prevent and/or ameliorate the morbidity, mortality and dissemination of this emerging fungal pathogen. The research outlined in this proposal directly addresses this pressing need. We have discovered that the mannan which coats the outermost surface of C. auris clinical strains is both structurally and biologically unique, i.e. it contains two unique acid labile Mα1-PO4 side chains that are not found in other fungal mannans or other fungal pathogens. Thus, C. auris mannan distinguishes it from virtually all other fungal pathogens. This suggests that C. auris mannan represents a target of opportunity for the development of a C. auris vaccine. We hypothesize that the dual Mα1-PO4 mannan structure can be used to develop a C. auris vaccine that will be effective against multiple C. auris strains. The goals of this R21 proposal are to: i) evaluate the efficacy of the vaccine in a murine model of C. auris infection and ii) evaluate the anti-fungal immune response to the vaccine. To address these objectives we propose two specific aims. Aim 1. Evaluate the efficacy of a C. auris mannan based vaccine formulation against systemic C. auris infection. Aim 2. Assess innate and adaptive immune responses elicited by the C. auris mannan vaccine.

金黄色念珠菌是一种真菌病原体，已被鉴定为一种新发传染病和公众 对健康的威胁。金黄色葡萄球菌因其对抗真菌治疗的耐药性、传播性和高死亡率而闻名。 以及其殖民患者、医护人员和医疗环境的能力。C.Auris菌株是 通常对氟康唑耐药，大约一半的金黄色葡萄球菌菌株对两种或两种以上的抗真菌药物耐药 毒品。金黄色葡萄球菌引起医院内侵袭性念珠菌病暴发，死亡率约为60%。一共有五个 不同的Auris分支，所有的分支似乎都是从1996年开始进化的。除耐药外，C. 金黄色葡萄球菌可以在皮肤上定居，在人与人之间传播，并在医疗保健环境中长期存活 时间到了。这些特征是奥里斯所特有的。C.Auris对许多标准去污试剂和 这导致了这种病原体在世界各地的迅速传播。这使它成为一种 特别危险的新出现的真菌病原体。因此，奥里斯是第一个真菌也就不足为奇了。 已被确认为公共健康威胁的病原体。现在需要的是一种针对奥氏杆菌的疫苗，它可以 预防和/或改善这种新出现的真菌病原体的发病率、死亡率和传播。这个 这项提案中概述的研究直接解决了这一紧迫需求。我们发现，甘露聚糖 它覆盖在金黄色葡萄球菌临床菌株的最外面，在结构和生物学上都是独一无二的，即它 含有两个独特的酸不稳定的Mα1-PO4侧链，这是其他真菌甘露糖或其他真菌中没有的 病原体。因此，金黄色葡萄球菌甘露聚糖将其与几乎所有其他真菌病原体区分开来。这表明C. 奥里斯·甘露聚糖是发展奥氏弧菌疫苗的一个机会目标。我们假设 双Mα1-PO4甘露聚糖结构可用于研制有效的金黄色葡萄球菌疫苗。 多株金黄色葡萄球菌。R21提案的目标是：i)评估疫苗在小鼠身上的效力 建立金黄色葡萄球菌感染模型，评价疫苗的抗真菌免疫应答。要解决这些问题 目标我们提出两个具体目标。目的1.评价以甘露聚糖为基础的疫苗的效果 针对系统性金黄色葡萄球菌感染的配方。目标2.评估先天和获得性免疫反应 金黄色葡萄球菌甘露聚糖疫苗。