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: 8660024
• 负责人: Karen Patricia Day
• 金额: $ 27万
• 依托单位: UNIVERSITY OF MELBOURNE
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660024
• 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; 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）：恶性疟原虫疟疾的负担是巨大的，每年有多达一百万人死亡，数十亿人感染并持续数月。这些慢性感染大多无症状，是感染源，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镜观察来测量感染的水库。然而，该方法不敏感，并且不能捕获物种内的变异以准确地评估恶性疟原虫的真实储库，其中疟疾流行区的个体携带多种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（PfEMP 1），这是一种在无性寄生虫阶段和传播阶段感染的红细胞表面表达的分子。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抗原变异的基础。这种转换表面抗原变体的能力使疟原虫能够逃避宿主的免疫反应，建立慢性感染，以优化对蚊子的传播。在不同的寄生虫基因组中存在不同的var基因库。这种库多样性被提议允许在暴露的宿主中建立、持续和传播重复感染。因此，var基因多样性提供了一个具体的诊断措施的大小以及潜在的持久性或持续时间的水库的感染在流行地区。该建议的总体目标是了解var基因的进化，以提高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线var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，这些环境中的每一个都显示出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与定制的统计和生物信息学开发在过去的6年里由天实验室来描述var基因的群体遗传学。此外，我们将分析微卫星多样性作为当地寄生虫种群结构的标志。重要的假设-相对于全球水平，var多样性的地理变异存在于地方水平-将被检验，因为这样的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，以便以比现有方法更复杂的方式减少疟疾感染的宿主。这是一个重要的“跨学科”自然史实验，类似于定义流感疾病监测中血凝素分子的变异，除了由于每个基因组的多个高度多样的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var多样性来确定感染源是疟疾控制的关键一步。

项目成果

Evolutionary structure of Plasmodium falciparum major variant surface antigen genes in South America: Implications for epidemic transmission and surveillance.

• DOI: 10.1002/ece3.3425
• 发表时间: 2017-11
• 期刊: Ecology and evolution
• 影响因子: 2.6
• 作者: Rougeron V;Tiedje KE;Chen DS;Rask TS;Gamboa D;Maestre A;Musset L;Legrand E;Noya O;Yalcindag E;Renaud F;Prugnolle F;Day KP
• 通讯作者: Day KP

Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana.

识别来自加纳当地社区的恶性疟原虫的不同重组抗原 var 基因中的功能组。

• DOI: 10.1371/journal.pcbi.1006174
• 发表时间: 2018
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Rorick,MaryM;Baskerville,EdwardB;Rask,ThomasS;Day,KarenP;Pascual,Mercedes
• 通讯作者: Pascual,Mercedes

Evolutionary analyses of the major variant surface antigen-encoding genes reveal population structure of Plasmodium falciparum within and between continents.

• DOI: 10.1371/journal.pgen.1009269
• 发表时间: 2021-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Tonkin-Hill G;Ruybal-Pesántez S;Tiedje KE;Rougeron V;Duffy MF;Zakeri S;Pumpaibool T;Harnyuttanakorn P;Branch OH;Ruiz-Mesía L;Rask TS;Prugnolle F;Papenfuss AT;Chan YB;Day KP
• 通讯作者: Day KP

Indoor residual spraying with a non-pyrethroid insecticide reduces the reservoir of Plasmodium falciparum in a high-transmission area in northern Ghana.

使用非拟除虫菊酯杀虫剂进行室内滞留喷洒可减少加纳北部高传播地区恶性疟原虫的储存量。

• DOI: 10.1371/journal.pgph.0000285
• 发表时间: 2022
• 期刊: PLOS global public health
• 作者: Tiedje,KathrynE;Oduro,AbrahamR;Bangre,Oscar;Amenga-Etego,Lucas;Dadzie,SamuelK;Appawu,MaxwellA;Frempong,Kwadwo;Asoala,Victor;Ruybal-Pésantez,Shazia;Narh,CharlesA;Deed,SamanthaL;Argyropoulos,DionneC;Ghansah,Anita;Agyei,Samu
• 通讯作者: Agyei,Samu

Population genomics of virulence genes of Plasmodium falciparum in clinical isolates from Uganda.

• DOI: 10.1038/s41598-017-11814-9
• 发表时间: 2017-09-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Ruybal-Pesántez S;Tiedje KE;Tonkin-Hill G;Rask TS;Kamya MR;Greenhouse B;Dorsey G;Duffy MF;Day KP
• 通讯作者: Day KP