Variant surface antigens in cerebral malaria pathogenesis

脑型疟疾发病机制中的变异表面抗原

基本信息

批准号：
9019218
负责人：
Steven A. Fisher
金额：
$ 47.69万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9019218
关键词：
Acute Africa South of the Sahara Anemia Animal Model Antibodies Antibody Formation Anticoagulation Antigens Autopsy Binding Blood Vessels Blood capillaries Brain CD36 gene Cardiovascular system Case-Control Studies Cerebral Malaria Child Clinical Collaborations Communities Convalescence Custom Cytoprotection Data Development Erythrocyte Membrane Erythrocytes Family Functional disorder Gene Family Genes Genetic Genome Genomics Goals Human Hypoxia Immune Immune system Immunity Individual Infection Inflammation Kidney Failure Lead Life Link Malaria Malaria Vaccines Mali Measures Mediating Membrane Membrane Proteins Mus Natural Immunity Open Reading Frames Organ Parasites Pathogenesis Pathway interactions Patients Plasmodium falciparum Play Protein C Protein Family Protein Fragment Protein Microchips Proteins Proteomics Reporter Research Research Technics Respiratory distress Role Rural Sampling Serum Severities Site Spleen Subgroup Surface Surface Antigens Syndrome System Vaccines Variant Vascular Diseases Virulence Work abstracting activated protein C receptor brain tissue capillary case control cerebrovascular killings mouse model next generation sequencing novel parasite genome prevent public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): Cerebral malaria is the deadliest form of malaria, potentially killing half of its victims-primarily children in sub- Saharan Africa. However, most children in malaria-endemic regions appear to develop immunity to severe malaria early in life, a phenomenon that correlates with the production of antibodies to malaria parasite antigens that are expressed on the surface of infected erythrocytes. These variant surface antigens (VSAs) are the most polymorphic families within the parasite genome: Plasmodium falciparum erythrocyte membrane proteins (PfEMP1), repetitive interspersed family proteins (RIFINs) and the sub-telomeric variable open reading frame proteins (STEVORs). Each malaria genome has hundreds of genes encoding these diverse parasite surface antigens, of which only a small subset are expressed on the surface of a given infected erythrocyte. If a subset of VSAs is specific to cerebral malaria, they would be an important target for a malaria vaccine to protect children and travelers from the deadliest consequences of malaria. Work at our field site in rural Mali suggests that malaria parasites express a "stealth" subgroup of these parasite surface antigens more commonly in cerebral malaria than in milder forms of malaria. Our overall goals are to determine the VSA contribution to the pathophysiology of cerebral malaria and the importance of an individual's development of antibodies to VSAs in the acquisition of immunity to cerebral malaria. This project combines novel genomic and proteomic approaches with the use of a new animal model to measure the association between particular variant surface antigens and the development of cerebral malaria and also protective natural immunity. We will determine the genetic sequences of VSAs in cerebral malaria infections and in matched uncomplicated malaria controls in a cerebral malaria case-control study and ascertain which VSAs are found on the surface on infected erythrocytes (Aim 1). Mice will be infected with these field-derived parasites and the microvascular pathophysiological effects will be identified in the brain, including associations with expressed VSAs (Aim 2). Multiple VSA fragments will be encoded onto microarray chips, which will then be exposed to patients' sera to study antibody interactions with all of these proteins at once (Aim 3). This project introduces cutting-edge research techniques-some from outside the malaria research community-including next-generation sequencing, custom microarrays, proteomics, and a promising new animal model, to advance our understanding of cerebral malaria and the development of a cerebral malaria vaccine.

描述（由申请人提供）：脑型疟疾是最致命的疟疾，可能导致一半的受害者死亡，主要是撒哈拉以南非洲地区的儿童。然而，疟疾流行地区的大多数儿童似乎在生命早期就对严重疟疾产生了免疫力。，这种现象与感染红细胞表面表达的疟疾寄生虫抗原抗体的产生有关。这些变异表面抗原（VSA）是寄生虫中最具多态性的家族。基因组：恶性疟原虫红细胞膜蛋白（PfEMP1）、重复散布家族蛋白（RIFIN）和亚端粒可变开放阅读框蛋白（STEVOR）每个疟疾基因组都有数百个编码这些不同寄生虫表面抗原的基因。如果 VSA 的一个子集是脑型疟疾特有的，那么它们将是疟疾的重要靶标。我们在马里农村地区的实地工作表明，与较温和的疟疾相比，疟疾寄生虫在脑型疟疾中更常见地表达这些寄生虫表面抗原的“隐形”亚群。目标是确定 VSA 对脑型疟疾病理生理学的贡献以及个体开发 VSA 抗体在获得脑型疟疾免疫力中的重要性。该项目将新颖的基因组学和蛋白质组学方法与使用相结合。建立一种新的动物模型来测量特定变异表面抗原与脑型疟疾的发展以及保护性自然免疫之间的关联我们将确定脑型疟疾感染和脑型疟疾病例中匹配的无并发症疟疾控制中的 VSA 的基因序列。对照研究并确定在受感染的红细胞表面发现了哪些 VSA（目标 1），小鼠将被这些来自野外的寄生虫感染，并且将确定大脑中的微血管病理生理学影响，包括多个 VSA 片段将被编码到微阵列芯片上，然后将其暴露于患者血清中，以立即研究抗体与所有这些蛋白质的相互作用（目标 3）。研究技术（一些来自疟疾研究界之外），包括下一代测序、定制微阵列、蛋白质组学和有前途的新动物模型，以增进我们对脑型疟疾的理解和脑型疟疾疫苗的开发。