P.falciparum var gene diversity and malaria control

恶性疟原虫基因多样性与疟疾控制

• 批准号: 8463969
• 负责人: Karen Patricia Day
• 金额: $ 39.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463969
• 关键词: Accounting; Africa South of the Sahara; African; Age; Antigenic Variation; Antigens; Area; Binding; Bioinformatics; Biology; Blood; Cessation of life; Child; Chronic; Complex; Culicidae; Custom; Data; Data Set; Diagnostic; Disease; Epidemiology; Erythrocyte Membrane; Erythrocytes; Evaluation; Event; Evolution; Exposure to; Falciparum Malaria; Frequencies; Gabon; Gene Structure; Generations; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Genotype; Goals; HIV; Hemagglutinin; Human; Imagery; Immune; Immune response; Immunity; Individual; Infection; Influenza; Influenza Hemagglutinin; Knowledge; Laboratories; Longitudinal Studies; Malaria; Malaria Vaccines; Measures; Mediating; Melanesia; Membrane Proteins; Methods; Microsatellite Repeats; Microscopic; Modeling; Molecular; Molecular Epidemiology; Multigene Family; Natural History; Papua New Guinea; Parasites; Pattern; Peru; Plasmodium falciparum; Play; Population; Population Dynamics; Population Genetics; Recording of previous events; Relative (related person); Role; Sampling; Sequence Analysis; Site; South America; Staging; Statistical Models; Structure; Suggestion; Surface; Surface Antigens; Surveys; Testing; Tissue-Specific Gene Expression; Universities; Vaccines; Variant; Virulence; Work; acquired immunity; asexual; base; cross immunity; design; geographic difference; geographic population; geographically distant; improved; novel; parasite genome; population movement; population survey; public health relevance; research study; statistics; superinfection; theories; tool; transmission process; vector

DESCRIPTION (provided by applicant): The burden of Plasmodium falciparum malaria is enormous with up to a million deaths per annum and billions of infections that persist for many months in the human population. These chronic infections, largely asymptomatic, constitute the reservoir of infection and serve to fuel continued malaria transmission. Traditionally, the reservoir of infection has been measured in population surveys by microscopic visualization of the parasite in blood smears. This method, however, is not sensitive and does not capture within species variation to accurately assess the true reservoir of P. falciparum where individuals in malaria endemic areas carry multiple distinct parasite genomes. The var multigene family encodes P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1), a molecule that is expressed on the surface of erythrocytes infected by asexual parasite stages and transmission stages. There are 50-60 var genes in a P. falciparum genome and differential expression of these genes underlies clonal antigenic variation. This ability to switch surface antigen variants allows the malaria parasite to evade the host immune response and establish chronic infection to optimize transmission to the mosquito. Diverse repertoires of var genes exist in different parasite genomes. This repertoire diversity is proposed to allow a superinfection to establish, persist, and transmit in an exposed host. Thus, var gene diversity gives a specific diagnostic measure of the size as well as the potential for persistence or duration of the reservoir of infection in an endemic area. The overall goal of this proposal is to understand the evolution of var genes in order to improve molecular surveillance of P. falciparum. To achieve this goal, we need to collect baseline var diversity data in three global settings: sub- Saharan Africa, Melanesia, and South America. Each of these settings displays a distinct epidemiology of malaria due to differences including vector biology, transmission intensity and population history. We will use a standardized molecular epidemiology framework with custom made statistics and bioinformatics developed over the past 6 years by the Day laboratory to describe the population genetics of var genes. In addition, we will analyze microsatellite diversity as a marker for local parasite population structure. The important hypothesis--that geographic variation in var diversity exists at a local level relative to global level--will be tested as such population structure would influence cross-immunity among parasite populations. Moreover, such structure would dramatically influence the approach to developing and assessing elimination and eradication strategies to reduce the reservoir of malaria infection in a more sophisticated manner than existing methods. This is an important "interdisciplinary" natural history experiment, akin to defining variation in the hemagglutinin molecule for influenza disease surveillance, except that the var genetics is more complex due to the multiple, highly diverse var copies per genome and possibilities for recombination. Defining the reservoir of infection by measuring var diversity is a critical step for malaria control in the new era of malaria eradication.

描述(由申请人提供)：恶性疟疾的负担是巨大的，每年有多达100万人死亡，数十亿人感染，在人类人口中持续数月。这些大部分无症状的慢性感染构成了感染的宿主，并助长了疟疾的持续传播。传统上，在人口调查中，通过血液涂片中寄生虫的显微可视化来测量感染的宿主。然而，这种方法不敏感，也不能捕捉到物种变异，以准确评估恶性疟原虫的真实储存库，疟疾流行区的个体携带多个不同的寄生虫基因组。Var多基因家族编码恶性疟原虫红细胞膜蛋白-1(PfEMP1)，该分子表达于感染无性寄生虫期和传播期的红细胞表面。恶性疟原虫基因组中有50-60个var基因，这些基因的差异表达是克隆性抗原变异的基础。这种切换表面抗原变体的能力使疟疾寄生虫能够逃避宿主的免疫反应，并建立慢性感染，以优化对蚊子的传播。不同寄生虫基因组中存在不同的var基因谱系。这种谱系多样性的提出是为了允许重叠感染在暴露的宿主中建立、持续和传播。因此，var基因多样性提供了一种特定的诊断措施，可以衡量流行地区感染宿主的大小以及持续或持续的可能性。这项建议的总体目标是了解var基因的进化，以改善对恶性疟原虫的分子监测。为了实现这一目标，我们需要在三个全球环境中收集基准变量多样性数据：撒哈拉以南非洲、美拉尼西亚和南美洲。由于病媒生物学、传播强度和人口历史等方面的差异，每一种环境都显示了不同的疟疾流行病学。我们将使用一个标准化的分子流行病学框架，结合戴实验室在过去6年中开发的定制统计和生物信息学来描述var基因的群体遗传学。此外，我们将分析微卫星多样性，以此作为当地寄生虫种群结构的标志。重要的假设--变种多样性的地理差异存在于局部水平相对于全球水平--将得到检验，因为这种种群结构将影响寄生虫种群之间的交叉免疫。此外，这种结构将极大地影响制定和评估消除和根除战略的方法，以比现有方法更复杂的方式减少疟疾感染者。这是一个重要的“跨学科”自然历史实验，类似于定义用于流感疾病监测的血凝素分子的变异，不同之处在于，由于每个基因组有多个高度多样化的var拷贝和重组的可能性，var遗传学更加复杂。在消灭疟疾的新时代，通过测量变异性来确定感染源是疟疾控制的关键一步。