Babesiosis: An Emerging Infectious Threat to Transfusion Medicine

巴贝斯虫病：对输血医学的新的感染威胁

• 批准号: 8243503
• 负责人: Cheryl Ann Lobo
• 金额: $ 41.05万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243503
• 关键词: Affinity; Animals; Antibodies; Antigens; Apical; Appearance; Babesia; Babesia microti; Babesiosis; Binding; Biological Assay; Blood; Blood Screening; Blood Transfusion; Blood donor screening; Carbohydrates; Cattle; Cell physiology; Cells; Communicable Diseases; Confocal Microscopy; DNA; Development; Diagnosis; Diagnostic; Enzymes; Epidemiology; Erythrocytes; Event; Gel; Gene Deletion; Genes; Glycophorin; Glycophorin A; Glycophorin B; Glycoside Hydrolases; Goals; Human; Immunofluorescence Immunologic; Immunoglobulin Fragments; Immunoprecipitation; In Vitro; Infection; Intervention; Knowledge; Ligand Binding; Ligands; Malaria; Medicine; Membrane Proteins; Methodology; Methods; Microscopic; Molecular; New York; Organelles; Parasites; Parasitic infection; Pattern; Peptide antibodies; Peptides; Physiologic pulse; Play; Prevention; Process; Proteins; Reagent; Recombinant Proteins; Recombinants; Reporting; Rodent; Role; Safety; Screening procedure; Surface; System; Testing; Tight Junctions; Transfection; Transfusion; Western Blotting; Zoonoses; blood product; cDNA Library; experience; extracellular; in vitro Assay; interest; man; mutant; neglect; new therapeutic target; novel; parasite invasion; pathogen; public health relevance; receptor; sugar; tool; transmission process

DESCRIPTION (provided by applicant): Babesiosis is a zoonosis, a disease communicable from animals to man. The rodent parasite, Babesia microti and the bovine pathogen, Babesia divergens are responsible for most of the human infections that have been reported to date, globally. From a blood safety perspective, transfusion-transmitted infections involving Babesia spp. have become increasingly problematic in the USA, with progressively more reported each year. Therefore the study of this blood-borne parasite should be considered as a priority for transfusion medicine. Our purpose is to understand the invasion process of B. divergens into the human red blood cell (RBC), with the ultimate aim of exploiting parasite molecules found to play key roles in invasion as diagnostic and blood screening tools. The in-vitro system that we use for studying invasion of the human red cell by B. divergens, permits direct exploration of the events associated with parasite invasion of the human RBC, using viable merozoites of B. divergens. Molecules on the surface of the parasite and those secreted by apical organelles function at the host/parasite interface, and we need to identify them and determine their interactions and function, if we are to define the steps in the invasion mechanism and identify new therapeutic targets. We have identified one such putative RBC binding ligand, Bd30 and the focus of our project is the study of its interaction with the RBC, specifically the glycophorins, during parasite invasion. There are three specific aims in this proposal (1) To characterize glycophorin A (GPA) and glycophorin B (GPB) as RBC receptors for B. divergens invasion (2) To validate Bd30 as the B. divergens ligand that binds glycophorin A (GPA) and/or glycophorin B (GPB) and to characterize Bd30 in the parasite and (3) To evaluate the functional significance of the interaction between GPA and/or GPB and Bd17 in merozoite invasion. Methodology that is proposed includes inhibition of invasion assays using specific enzyme treatments of the RBC, mutant cells lacking defined RBC antigens and the use of antibodies and competitor peptides; erythrocyte binding assays using native and recombinant Bd30 ligand protein and antibodies against Bd30 in invasion assays, as well as proposed gene deletion to study its function. Thus, the major goal of the project is to elucidate the molecular mechanisms involved in the entry of B. divergens merozoites into the erythrocyte. It is anticipated that studies detailed in this proposal will result in reagents for diagnosis, epidemiology and treatment and prevention of human babesiosis, and assist in developing products to screen blood products. PUBLIC HEALTH RELEVANCE: Babesiosis is a zoonosis, a disease communicable from animals to man and an important blood-borne human parasitic infection. Human to human transmission of the parasite is well recognized to occur through blood transfusion. Despite being a significant threat to the safety of blood transfusions, its study has largely been neglected. The long term objective of the present proposal is to develop a detailed mechanistic understanding of the erythrocytic invasion of the B. divergens parasite in order to develop novel therapies for treating the infection and effective strategies for screening of blood donors for babesia infection. We are specifically looking at interactions between the RBC receptors, glycophorins A and B and the Babesia molecules that bind to them so that we can define the steps in the invasion mechanism. Recognizing that Babesia is an expanding blood safety threat we are interested in the development of viable interventions to detect and halt transmission of these pathogens via blood transfusions.

描述（由申请人提供）：Babesiosis是人畜共患病，是一种从动物到人的疾病。啮齿动物寄生虫，贝贝西亚（Babesia Microti）和牛病原体，巴比西亚（Babesia Divergens）负责迄今已据报道的大多数人类感染。从血液安全的角度来看，输血传播的感染涉及巴比西亚属。在美国，越来越多的问题，每年逐渐报告。因此，对这种血源性寄生虫的研究应被视为输血医学的优先事项。我们的目的是了解芽孢杆菌对人类红细胞（RBC）的入侵过程，其最终目的是利用发现在诊断和血液筛查工具中发现关键作用的寄生虫分子。我们使用的烟草芽孢杆菌用于研究人类红细胞侵袭的体外系统，可以直接探索与寄生虫入侵人类RBC相关的事件，并使用可行的B. divergens的可行蛋白酶。如果要定义入侵机制中的步骤并确定新的治疗靶标，则寄生虫表面的分子和顶端细胞器的作用的分子在宿主/寄生虫界面上的作用。我们已经确定了一种这种推定的RBC结合配体BD30，而我们项目的重点是在寄生虫入侵期间研究了其与RBC的相互作用，特别是糖酚蛋白。该提案（1）中有三个具体目的是表征糖蛋白A（GPA）和糖素B（GPB）作为B. divergens入侵（2）的RBC受体，以验证BD30作为B. divergens b. divergens的配体，可与糖蛋白A（GPA）A（GPA）和//clycophorin and dy parsize and bd（GPA）和GPB（GPB）（gpba）和GPB（GPB）（gpba）bd（ （3）评估Merozoite入侵中GPA和/或GPB和BD17之间相互作用的功能意义。拟议的方法包括使用RBC的特定酶处理，缺乏定义的RBC抗原的突变细胞以及抗体和竞争者肽的使用；使用天然和重组BD30配体蛋白和抗BD30抗体的红细胞结合测定在入侵测定中，以及提出的基因缺失来研究其功能。因此，该项目的主要目的是阐明参与进入红细胞的分子机制。可以预料，该提案中详细介绍的研究将导致诊断，流行病学和治疗和预防人类Babesiosis的试剂，并协助开发产品以筛选血液产品。 公共卫生相关性：巴布西病是人畜共患病，是一种从动物到人传播的疾病，以及重要的血源性血液寄生寄生虫感染。人类到人类传播寄生虫的传播是通过输血发生的。尽管对输血的安全构成了重大威胁，但其研究在很大程度上被忽略了。本提案的长期目标是对B. divergens寄生虫的红细胞侵袭进行详细的机理理解，以开发用于治疗感染的新疗法和有效的策略，以筛查贝贝西亚感染的献血者。我们专门研究了RBC受体，糖蛋白A和B和与它们结合的Babesia分子之间的相互作用，以便我们可以定义入侵机制中的步骤。认识到巴比西亚是一种不断扩大的血液安全威胁，我们对开发可行的干预措施感兴趣，以通过输血来检测和停止这些病原体的传播。