P.falciparum var gene diversity and malaria control

恶性疟原虫基因多样性与疟疾控制

基本信息

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
项目类别：
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

项目摘要

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）：恶性疟疾疟原虫的负担巨大，每年多达一百万人死亡和数十亿个感染，这些感染在人口中持续了数月。这些慢性感染（在很大程度上无症状）构成了感染的储层，并为持续的疟疾传播供电。传统上，通过血液涂片中寄生虫的微观可视化，在人口调查中测量了感染的储层。然而，该方法不敏感，也不会在物种变化中捕获以准确评估恶性疟原虫的真实储层，在疟疾中流行地区的个体具有多种不同的寄生虫基因组。 Var Multigene家族编码恶性疟原虫红细胞膜蛋白-1（PFEMP1），这是一种在被无性寄生虫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。这种切换表面抗原变异的能力使疟疾寄生虫能够逃避宿主免疫反应并建立慢性感染以优化向蚊子的传播。 VAR基因的多种曲目存在于不同的寄生虫基因组中。提出了这种曲目多样性，以允许超级感染在暴露的宿主中建立，持久和传播。因此，VAR基因的多样性给出了特定的诊断度量，以及在流行区域中感染储层的持久性或持续时间的潜力。该提案的总体目标是了解VAR基因的演变，以改善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静脉曲张数据：撒哈拉以南非洲，美拉尼亚和南美。这些环境中的每一个都显示出疟疾的独特流行病学，这是由于媒介生物学，传播强度和人口历史的差异。我们将使用标准化的分子流行病学框架，并在过去6年中通过day实验室开发的定制统计和生物信息学来描述VAR基因的种群遗传学。此外，我们将分析微卫星多样性作为局部寄生虫种群结构的标志。重要的假设 - 纳尔多样性的地理差异是在局部水平相对于全球水平的 - 将被测试，因为这种种群结构将影响寄生虫种群之间的跨免疫。此外，这种结构将极大地影响开发和评估消除和消除策略的方法，以比现有方法更复杂地减少疟疾感染的储层。这是一个重要的“跨学科”自然历史实验，类似于定义流感疾病监测的血凝素分子的变化，只是由于每个基因组的多个，高度多样的VAR拷贝和重新组合的可能性，VAR遗传学更为复杂。通过衡量从来的多样性来定义感染储层是在消除疟疾新时代的疟疾控制的关键步骤。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

Using expected sequence features to improve basecalling accuracy of amplicon pyrosequencing data.

使用预期的序列特征来提高扩增子焦磷酸测序数据的碱基识别准确性。