Variant surface antigens in cerebral malaria pathogenesis

脑型疟疾发病机制中的变异表面抗原

• 批准号: 9144853
• 负责人: Steven A. Fisher
• 金额: $ 43.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/9144853
• 关键词: Acute; Africa South of the Sahara; Anemia; Animal Model; Antibodies; Antibody Formation; Antibody-mediated protection; 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; Health; Human; Hypoxia; Immune; Immune system; Immunity; Individual; Infection; Inflammation; Kidney Failure; Lead; Life; Link; Malaria; Malaria Vaccines; Mali; Measures; 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; cerebral oxygenation; cerebrovascular; humanized mouse; killings; malaria infection; mouse model; next generation sequencing; novel; parasite genome; prevent; receptor; whole genome

 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（由适用提供）：脑疟疾是最致命的疟疾形式，可能杀死了撒哈拉以南非洲的一半受害者。然而，大多数疟疾 - 内态区域中的儿童似乎在生命的早期就会产生对严重疟疾的免疫力，这一现象与在感染红细胞表面表达的抗疟原虫抗原的抗体产生有关。这些变异的表面抗原（VSA）是寄生虫基因组中最多的多态性家族：恶性疟原虫红细胞膜细胞膜蛋白（PFEMP1），重复的散布家族蛋白（Rifins）和亚型型型蛋白质（Refters）。每个疟疾基因组都有数百个编码这些不同的寄生虫表面抗原的基因，其中只有一个小子集在给定感染的红细胞的表面上表达。如果VSA的一部分特定于脑疟疾，则它们将成为疟疾疫苗保护儿童和旅行者免受疟疾最致命后果的重要目标。在我们的野外马里的现场工作表明，疟疾寄生虫表达了这些寄生虫表面抗原的“隐形”亚组，而在脑疟疾中比在疟疾形式中更常见。我们的总体目标是确定VSA对脑疟疾的病理生理的贡献，以及个人对VSA抗体发展在获得脑疟疾的免疫方面的重要性。该项目将新型的基因组和蛋白质组学方法与使用新的动物模型来衡量特定变体表面抗原与大脑疟疾的发展之间的关联并保护自然免疫学之间的关联。我们将在脑疟疾病例对照研究中确定脑疟疾感染中VSA的遗传序列以及匹配的简单疟疾对照组中的遗传序列，并确定在感染的红细胞上发现了哪些VSA（AIM 1）。小鼠将感染这些野外衍生的寄生虫，在大脑中将发现微血管病理生理作用，包括与表达的VSA的关联（AIM 2）。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的血清，以一次研究与所有这些蛋白质的抗体相互作用（AIM 3）。该项目从疟疾研究社区之外介绍了尖端研究技术，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，以促进我们对大脑疟疾的了解和大脑疟疾疫苗的发展。