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（由申请方提供）：巴贝虫病是一种人畜共患病，是一种可从动物传染给人的疾病。啮齿类寄生虫小巴贝虫和牛病原体分歧巴贝虫是迄今为止全球报告的大多数人类感染的原因。从血液安全的角度来看，输血传播的巴贝虫感染。在美国已经变得越来越成问题，每年报道的越来越多。因此，对这种血液传播的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B的入侵过程。该研究的最终目的是利用在入侵中发挥关键作用的寄生虫分子作为诊断和血液筛查工具。本研究建立了体外研究B对人红细胞侵袭的实验系统。分歧者，允许使用B的活裂殖子直接探索与寄生虫侵入人RBC相关的事件。分歧者寄生虫表面的分子和顶端细胞器分泌的分子在宿主/寄生虫界面起作用，如果我们要定义入侵机制的步骤并确定新的治疗靶点，我们需要识别它们并确定它们的相互作用和功能。我们已经确定了这样一个假定的红细胞结合配体，Bd 30和我们的项目的重点是研究其相互作用的红细胞，特别是血型糖蛋白，在寄生虫入侵。本研究的目的有三：（1）鉴定血型糖蛋白A（GPA）和血型糖蛋白B（GPB）作为B的红细胞受体。（2）证实Bd 30为趋异侵袭的B。（3）探讨结合血型糖蛋白A（GPA）和/或血型糖蛋白B（GPB）的趋异配体与Bd 30的相互作用在裂殖子侵袭中的功能意义。所提出的方法包括使用RBC的特定酶处理的侵袭测定抑制、缺乏确定的RBC抗原的突变细胞以及使用抗体和竞争肽;在侵袭测定中使用天然和重组Bd 30配体蛋白和针对Bd 30的抗体的红细胞结合测定，以及提出的基因缺失以研究其功能。因此，该项目的主要目标是阐明参与B进入的分子机制。使裂殖子进入红细胞。预计本提案中详述的研究将产生用于诊断、流行病学和治疗及预防人类巴贝虫病的试剂，并有助于开发用于筛查血液制品的产品。 公共卫生相关性：巴贝斯虫病是一种人畜共患病，是一种可从动物传染给人的疾病，也是一种重要的血液传播的人类寄生虫感染。众所周知，人与人之间的寄生虫传播通过输血发生。尽管对输血安全性构成重大威胁，但其研究在很大程度上被忽视。本建议的长期目标是对B的红细胞侵袭形成详细的机制理解。为了开发用于治疗感染的新疗法和用于筛选献血者的巴氏疟原虫感染的有效策略，我们特别关注红细胞受体、血型糖蛋白A和B以及与它们结合的巴氏杆菌分子之间的相互作用，以便我们能够确定入侵机制的步骤。认识到巴氏杆菌是一种不断扩大的血液安全威胁，我们有兴趣开发可行的干预措施，以检测和阻止这些病原体通过输血传播。