Madagascar P. vivax Invasion of Duffy-negative Red Cells

马达加斯加间日疟原虫入侵达菲阴性红细胞

• 批准号: 8900911
• 负责人: PETER A. ZIMMERMAN
• 金额: $ 71.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900911
• 关键词: Address; Africa; African; Alleles; Antibodies; Antigens; Area; Binding; Binding Proteins; Biological; Biological Assay; Blood; Blood Group Antigens; Blood typing procedure; Cambodia; Cells; Cellular biology; Child; Classification; Clinical; Cloning; Code; Collaborations; Communities; Coupled; DNA Sequence; DNA Sequence Analysis; Data; Diagnosis; Disease; Enzymes; Epidemiology; Erythrocytes; Evolution; Exhibits; Exposure to; Flow Cytometry; Genbank; Gene Proteins; Genes; Genetic Population Study; Genotype; Goals; Health; High Prevalence; Human; In Vitro; Individual; Infection; Laboratories; Lead; Life; Ligand Binding; Ligands; Madagascar; Malaria; Methods; Microsatellite Repeats; Molecular; Molecular Biology; Mono-S; Monoclonal Antibodies; Parasites; Pathway interactions; Patients; Phenotype; Plasmodium vivax; Population; Population Study; Predisposition; Proteins; Recombinants; Relative (related person); Reporting; Research; Resistance; Reticulocytes; Risk; School-Age Population; Sequence Analysis; Specificity; Staging; Surveys; Testing; Variant; Vivax Malaria; antigen binding; apical membrane; base; blood group; drug efficacy; genome sequencing; in vivo; insight; interest; next generation sequencing; programs; promoter; success; transmission process

DESCRIPTION (provided by applicant): Today at least 2.6 billion people live in areas of risk for Plasmodium vivax transmission; 106 - 313 million cases of vivax malaria annually. While Duffy blood group negativity (Duffy (-)) has been considered to confer resistance to vivax malaria, our recent findings show that P. vivax has gained the capacity to infect erythrocytes and cause disease in Duffy (-) people in Madagascar. Our surveys of school-aged children revealed P. vivax PCR-positivity in 8.8% of asymptomatic Duffy (-) children. We also observed mono-infection P. vivax clinical disease in 4.9% of Duffy (-) people who reported for treatment during in vivo drug efficacy surveys; blood smear diagnosis confirmed P. vivax. Interestingly, preliminary population studies using 6 unlinked microsatellite markers suggested that Duffy (-) infections were caused by multiple P. vivax strains. While our results indicate that P. vivax invasion in Madagascar can occur independent of the erythrocyte's Duffy blood group antigen, we do not know if invasion is dependent or independent of the parasite's 'so-called' Duffy binding protein (PvDBP), the parasite ligand considered essential for invasion of human red blood cells. By DNA sequencing the PvDBP locus we have identified one allele to be over-represented in Duffy (-) infections. Additionally, recent whole genome sequencing has revealed that Malagasy P. vivax strains (and no P. vivax strains outside Madagascar) carry a PvDBP duplication. Overall, our findings suggest that P. vivax in Madagascar is evolving new erythrocyte infection mechanisms. To begin understanding how P. vivax has gained capacity to infect Duffy(-) erythrocytes we propose to study population genetic features of the parasite population while performing in-depth cell and molecular biological analysis of P. vivax strains of Madagascar. Resulting data from these studies will allow us to address the following Specific Aims. Aim 1 - Determine associations between P. vivax strains and susceptibility of Duffy (-) people to P. vivax blood-stage infection and clinical malaria. Aim 2 - Assess interactions between P. vivax erythrocyte binding ligands and human erythrocytes that influence merozoite attachment and human red cell invasion. Aim 3 - Test alternative invasion pathways of Malagasy P. vivax strains in vitro for Duffy (-) and Duffy (+) erythrocytes. Our studies will determine differential susceptibility of Duffy (+) and Duffy (-) people to P. vivax disease. Planne in vitro studies will provide insight regarding new P. vivax erythrocyte invasion mechanisms, with special emphasis on Duffy-independent invasion. Finally, we will determine whether molecular variations involved in P. vivax binding to, and invasion of Duffy (+) and Duffy (-) erythrocytes indicates capacity of Madagascar P. vivax strains to spread into other populations.

描述（由申请人提供）：今天，至少有26亿人生活在间日疟原虫传播风险地区；每年有1.06 - 3.13亿间日疟疾病例。虽然达菲（Duffy）血型阴性（Duffy(-)）被认为赋予了对间日疟的抗性，但我们最近的研究结果表明，间日疟原虫已经获得了感染红细胞并导致马达加斯加达菲（-）人患病的能力。我们对学龄儿童的调查显示8.8%的无症状达菲儿童中间日疟原虫pcr阳性。我们还观察到，在体内药物疗效调查中报告接受治疗的Duffy（-）患者中有4.9%出现单感染间日疟原虫临床疾病；血液涂片诊断证实间日疟原虫。有趣的是，使用6个非连锁微卫星标记进行的初步群体研究表明，Duffy（-）感染是由多种间日疟原虫菌株引起的。虽然我们的研究结果表明间日疟原虫在马达加斯加的入侵可以独立于红细胞的Duffy血型抗原发生，但我们不知道入侵是否依赖于寄生虫的“所谓的”Duffy结合蛋白（PvDBP），这种寄生虫配体被认为是入侵人类红细胞所必需的。通过PvDBP基因座的DNA测序，我们已经确定了一个在达菲（-）感染中过度代表的等位基因。此外，最近的全基因组测序显示马达加斯加间日疟原虫毒株（马达加斯加以外没有间日疟原虫毒株）携带PvDBP重复。总之，我们的发现表明马达加斯加的间日疟原虫正在进化出新的红细胞感染机制。为了开始了解间日疟原虫如何获得感染达菲（-）红细胞的能力，我们建议研究寄生虫种群的种群遗传特征，同时对马达加斯加间日疟原虫菌株进行深入的细胞和分子生物学分析。这些研究的结果数据将使我们能够解决以下具体目标。目的1 -确定间日疟原虫毒株与达菲人对间日疟原虫血期感染和临床疟疾的易感性之间的关系。目的2 -评估间日疟原虫红细胞结合配体与人红细胞之间的相互作用，这些相互作用影响子体附着和人红细胞入侵。目的3 -检测间日疟原虫对Duffy（-）和Duffy（+）红细胞的侵袭途径。我们的研究将确定Duffy（+）和Duffy（-）人群对间日疟原虫疾病的不同易感性。计划的体外研究将提供新的间日疟原虫红细胞入侵机制的见解，特别强调达菲独立入侵。最后，我们将确定间日疟原虫与Duffy（+）和Duffy（-）红细胞结合和入侵的分子变异是否表明马达加斯加间日疟原虫菌株传播到其他种群的能力。