The role of RIFINs and their interaction with blood type in vulnerability to severe malaria in Malian children

RIFIN 的作用及其与血型的相互作用在马里儿童易患严重疟疾方面的作用

基本信息

批准号：
10223427
负责人：
Albert E Zhou
金额：
$ 4.78万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-16 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223427
关键词：
ABO blood group system Acute Adhesives Affect Africa South of the Sahara Algorithms Anemia Antibodies Antigens Binding Bioinformatics Blood Case Fatality Rates Case-Control Studies Cells Cessation of life Child Coma Complex Custom Data Development Disease Disease Outcome Endothelial Cells Epidemiologic Methods Erythrocytes Family Functional disorder Genes Goals Grant High-Throughput Nucleotide Sequencing Immune Immune response Immunity Impairment In Vitro Individual Infection Infectious Disease Epidemiology Infectious Diseases Research Link Malaria Mali Mediating Microarray Analysis Natural Immunity Parasitemia Parasites Pathogenesis Physicians Plasmodium falciparum Play Predisposition Process Protein Microchips Proteins Receptor Cell Research Role Sampling Scientist Serum Shapes Site Spleen Subgroup Surface Surface Antigens Symptoms Technology Tissues Training Transcript Vaccine Design Vaccines Variant Virulence Factors Work acquired immunity career differential expression experience genomic epidemiology immune activation improved malaria infection next generation preference prevent public health intervention receptor reference genome sequencing platform skills transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Plasmodium falciparum causes nearly 435,000 deaths annually worldwide. Victims of severe malaria are predominantly sub-Saharan children, who may present with symptoms of severe anemia or unarousable coma. The pathogenesis of severe malaria is poorly understood but mediated by the expression of adhesive variant surface antigens (VSAs) on infected red blood cells. These VSAs are involved in sequestration and rosetting, unique virulence factors that allow the parasite to evade host immune responses and prevent clearance in the spleen. In particular, ABO blood groups are critical for rosetting, which is the spontaneous binding of infected and uninfected erythrocytes together. Individuals with blood type A are particularly vulnerable to severe malaria, unlike those with blood type O who appear relatively protected against severe disease. A relatively unstudied family of VSAs, the repetitive interspersed family (RIFIN) proteins, have been recently found to be important in rosetting. RIFINs preferentially bind blood type A antigens, forming larger and tighter rosettes than in blood type O. RIFINs may mediate the association between ABO blood type and severe malaria susceptibility; these proteins also appear to be targets for protective immunity. Humoral immune responses against RIFINs have been correlated with asymptomatic infections. As such, we posit that a subset of RIFINs play a critical role in severe malaria pathogenesis and that individuals who lack immunity to this subset are the most susceptible to develop severe malaria. In a case-control study that began in Mali in 2014, our group collected blood and serum samples from severe malaria cases and matched controls with uncomplicated malaria. Here, we propose to identify and sequence RIFINs expressed in severe malaria using next-generation RNA-sequencing technologies. Using a custom protein microarray, we will then determine whether a lack of antibodies to these RIFIN proteins is associated with developing severe disease. In Aim 1, we will identify subgroups of RIFIN transcripts that are differentially expressed in subjects with severe malaria versus matched controls with uncomplicated malaria via RNA-Seq. We hypothesize that a subset of RIFIN-As will be predominantly expressed in severe malaria cases with blood type A, in contrast to expression of a heterogeneous group of RIFIN-As in other infections. In Aim 2, we will use the predominant RIFIN transcripts identified in Aim 1 and other parasite antigens to populate a custom protein microarray in order to define a subset of RIFIN proteins associated with increased vulnerability to severe malaria. We hypothesize that sera from children acutely ill with severe malaria will recognize fewer RIFIN proteins on a protein microarray and react to them less intensely than their convalescent sera and sera from matched controls with uncomplicated malaria, particularly for severe malaria cases with blood type A. The candidate will gain valuable expertise in bioinformatics analysis, particularly from microarrays and transcriptomic data from high-throughput sequencing platforms; use epidemiological techniques to conduct translational infectious disease research; and apply these skills to support effective public health interventions such as a vaccine.

项目概要/摘要恶性疟原虫每年在全球造成近 435,000 人死亡。严重疟疾的受害者是主要是撒哈拉以南地区的儿童，他们可能会出现严重贫血或无法唤醒的昏迷症状。严重疟疾的发病机制尚不清楚，但它是由粘附变异体的表达介导的受感染红细胞上的表面抗原（VSA）。这些 VSA 参与隔离和玫瑰花结，独特的毒力因子，使寄生虫能够逃避宿主的免疫反应并阻止体内的清除脾。特别是，ABO 血型对于玫瑰花结至关重要，玫瑰花结是感染病毒的自发结合。和未感染的红细胞在一起。 A型血的人特别容易患上严重的疟疾，与 O 型血的人不同，O 型血的人似乎相对不会受到严重疾病的影响。一个相对未被研究的 VSA 家族，即重复散布家族 (RIFIN) 蛋白，最近被发现在玫瑰花结。 RIFIN 优先结合 A 型血抗原，形成比血型更大、更紧密的玫瑰花结 O. RIFINs 可能介导 ABO 血型与严重疟疾易感性之间的关联；这些蛋白质似乎也是保护性免疫的目标。针对 RIFIN 的体液免疫反应与无症状感染者相关。因此，我们认为 RIFIN 的一个子集在严重的疟疾发病机制，缺乏对该子集免疫力的个体最容易受到感染患上严重的疟疾。在 2014 年在马里开始的一项病例对照研究中，我们的团队收集了血液和血清来自严重疟疾病例的样本和与无并发症疟疾相匹配的对照样本。在此，我们建议使用下一代 RNA 测序技术对严重疟疾中表达的 RIFIN 进行识别和测序。然后，我们将使用定制的蛋白质微阵列来确定是否缺乏针对这些 RIFIN 蛋白质的抗体与发展严重疾病有关。在目标 1 中，我们将识别 RIFIN 转录本的亚组，这些亚组是患有严重疟疾的受试者与患有无并发症疟疾的匹配对照者之间存在差异表达 RNA测序。我们假设 RIFIN-As 的一个子集将主要在严重疟疾病例中表达具有 A 型血，与其他感染中异质 RIFIN-As 组的表达相反。在目标 2 中，我们将使用目标 1 中鉴定的主要 RIFIN 转录本和其他寄生虫抗原来填充自定义蛋白质微阵列，以确定与严重感染易感性增加相关的 RIFIN 蛋白质子集疟疾。我们假设患有严重疟疾的儿童的血清将识别较少的 RIFIN 蛋白在蛋白质微阵列上，对它们的反应不如恢复期血清和匹配血清强烈控制无并发症的疟疾，特别是 A 型血的严重疟疾病例。候选人将获得生物信息学分析方面的宝贵专业知识，特别是来自微阵列和转录组数据的知识高通量测序平台；利用流行病学技术进行转化传染疾病研究；并运用这些技能来支持有效的公共卫生干预措施，例如疫苗。