权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10012761
负责人：
Albert E Zhou
金额：
$ 3.91万
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 2023-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012761
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.

项目总结/文摘