Deciphering the roles of RIFIN and STEVOR parasite antigens in severe malaria pathogenesis via transcriptomics and immune profiling

通过转录组学和免疫分析破译 RIFIN 和 STEVOR 寄生虫抗原在严重疟疾发病机制中的作用

• 批准号: 10748822
• 负责人: Jonathan Lawton
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748822
• 关键词: Acute; Adherence; Africa South of the Sahara; African; Age; Amino Acid Sequence; Antibodies; Antibody Response; Antigens; Binding; Blood; Blood specimen; Blood typing procedure; Cell Surface Proteins; Cells; Cerebral Malaria; Child; Clinical; Clinical Research; Complex; Convalescence; Custom; Development; Disease; Epidemiologist; Erythrocyte Membrane; Erythrocytes; Falciparum Malaria; Family; Gene Expression; Generations; Genetic Polymorphism; Genome; Geographic Locations; Glycophorin C; Goals; Human; Immune; Immunity; Immunologic Epidemiology; In Vitro; Individual; Infection; International; Invaded; Investigation; Laboratory Study; Length; Link; Malaria; Malawi; Mali; Measures; Mediating; Mediator; Membrane Proteins; Messenger RNA; Molecular; Morbidity - disease rate; Open Reading Frames; Parasites; Pathogenesis; Pattern; Plasmodium falciparum; Predisposition; Preparation; Protein Family; Protein Microchips; Proteins; RNA; Research; Research Design; Risk; Risk Factors; Role; Sampling; Serology; Serum; Severities; Site; Subgroup; Surface; Surface Antigens; Symptoms; Syndrome; Therapeutic; Time; Training; Transcript; Uganda; Vaccines; Variant; Virulence; Vulnerable Populations; blood group; career; design; disease phenotype; immune clearance; malaria infection; malaria transmission; malarial anemia; mortality; next generation; novel strategies; preference; reference genome; response; skills; transcriptome sequencing; transcriptomics; vaccine development; Acute; Adherence; Africa South of the Sahara; African; Age; Amino Acid Sequence; Antibodies; Antibody Response; Antigens; Binding; Blood; Blood specimen; Blood typing procedure; Cell Surface Proteins; Cells; Cerebral Malaria; Child; Clinical; Clinical Research; Complex; Convalescence; Custom; Development; Disease; Epidemiologist; Erythrocyte Membrane; Erythrocytes; Falciparum Malaria; Family; Gene Expression; Generations; Genetic Polymorphism; Genome; Geographic Locations; Glycophorin C; Goals; Human; Immune; Immunity; Immunologic Epidemiology; In Vitro; Individual; Infection; International; Invaded; Investigation; Laboratory Study; Length; Link; Malaria; Malawi; Mali; Measures; Mediating; Mediator; Membrane Proteins; Messenger RNA; Molecular; Morbidity - disease rate; Open Reading Frames; Parasites; Pathogenesis; Pattern; Plasmodium falciparum; Predisposition; Preparation; Protein Family; Protein Microchips; Proteins; RNA; Research; Research Design; Risk; Risk Factors; Role; Sampling; Serology; Serum; Severities; Site; Subgroup; Surface; Surface Antigens; Symptoms; Syndrome; Therapeutic; Time; Training; Transcript; Uganda; Vaccines; Variant; Virulence; Vulnerable Populations; blood group; career; design; disease phenotype; immune clearance; malaria infection; malaria transmission; malarial anemia; mortality; next generation; novel strategies; preference; reference genome; response; skills; transcriptome sequencing; transcriptomics; vaccine development

PROJECT SUMMARY Despite decades of research, Plasmodium falciparum malaria continues to kill hundreds of thousands of children in sub-Saharan Africa each year. Vulnerability to severe malaria is complex, involving both host and parasite factors. Blood type A is an established risk factor for severe malaria, whereas blood type O is associated with protection from complicated symptoms. The exact mechanism of this phenomenon is incompletely understood but may involve interactions mediated by particular parasite antigens. RIFINs and STEVORs are highly diverse parasite protein families that are displayed on the surface of infected red blood cells. Recent laboratory studies suggest that these antigens may exacerbate malaria severity through multiple mechanisms, including adherence to nearby red blood cells to form “rosettes” that envelop the parasite and protect it from immune clearance. Certain RIFINs bind preferentially to type A red blood cells. STEVORs have a similar binding preference for glycophorin C, another red blood cell surface protein. These intriguing findings suggest that RIFINs and STEVORs may be central to P. falciparum virulence and drive differences in susceptibility to severe disease between blood types. Despite promising in vitro links to severe malaria vulnerability, the immense diversity of the RIFIN and STEVOR families has so far precluded the comprehensive study of these antigens in clinical infections. The goal of this proposal is to identify RIFIN and STEVOR subtypes that are associated with severe malaria in African children. We will obtain blood and serum samples from children with severe or non-severe malaria in Mali, Malawi, and Uganda, representing three regions of sub-Saharan Africa with distinct malaria transmission patterns. In Aim 1, we will identify the expressed rif and stevor transcripts in individual blood samples using reference-free RNA-Seq, then compare the abundance of transcript subgroups between severe and non-severe malaria. In Aim 2, we will profile antibody responses against a comprehensive microarray of RIFIN and STEVOR variants to identify immune “gaps” in children with severe malaria compared to non-severe malaria. RIFIN and STEVOR antigen subtypes that were preferentially expressed and/or not serorecognized in severe malaria infections may be important mediators of pathogenesis. RIFINs that predominate in severe cases with blood type A may be critical aspects of this group’s vulnerability. The proposed aims will help clarify the role of RIFINs and STEVORs in severe malaria pathogenesis and inform the development of tailored vaccines and therapeutics to protect the most at-risk children in sub-Saharan Africa. The applicant will develop and apply hands-on skills in transcriptomics, immunoepidemiology, and international clinical research design and management, critical to his intended career as a 21st century molecular epidemiologist.

项目摘要 尽管进行了数十年的研究，但恶性疟疾疟疾疟疾仍继续杀死成千上万的儿童 每年在撒哈拉以南非洲。严重疟疾的脆弱性很复杂，涉及宿主和寄生虫 因素。 A型A类型是严重疟疾的确定危险因素，而血型O则与 防止复杂症状。这种现象的确切机制尚不完全理解 但可能涉及特定的寄生虫抗原介导的相互作用。里弗斯和史蒂夫斯是高度潜水员 寄生虫蛋白家族显示在感染的红细胞表面上。最近的实验室研究 表明这些抗原可能通过多种机制加剧疟疾的严重程度，包括依从性 到附近的红细胞形成“玫瑰花结”，将寄生虫包膜并保护其免疫清除率。 某些Rifins优先结合键入红细胞。 Stevors对 糖蛋白C，另一种红细胞表面蛋白。这些有趣的发现表明Rifins和 Stevors可能是恶性疟原虫病毒的核心，并且在严重疾病的易感性方面具有差异 在血型之间。尽管有望在体外与严重的疟疾脆弱性联系在一起，但巨大 到目前为止 临床感染中的抗原。该建议的目的是识别Rifin和Stevor子类型 与非洲儿童的严重疟疾有关。我们将从儿童那里获得血液和血清样本 马里，马来和乌干达的严重或非重生疟疾，代表撒哈拉以南非洲的三个地区 具有独特的疟疾传播模式。在AIM 1中，我们将确定在 使用无参考RNA-Seq的单个血液样本，然后比较转录亚组的抽象 在严重和非重生疟疾之间。在AIM 2中，我们将针对全面的抗体反应介绍抗体反应 Rifin和Stevor变体的微阵列鉴定严重疟疾儿童的免疫“间隙” 致非严重的疟疾。 Rifin和Stevor抗原亚型优先表达和/或不表达 在严重的疟疾感染中被静止识别的可能是发病机理的重要介体。利芬 在严重的血液中，占主导地位可能是该组脆弱性的关键方面。提议 目的将有助于阐明里依林斯和Stevors在严重疟疾发病机理中的作用，并告知 开发量身定制的疫苗和治疗，以保护撒哈拉以南非洲最高风险的儿童。 申请人将在转录组学，免疫ePidemiology和International方面发展和运用动手技能 临床研究设计和管理，对他作为21世纪分子的意图职业至关重要 流行病学家。