Genetic analysis of cercarial release in schistosomes

血吸虫尾蚴释放的遗传分析

基本信息

批准号：
10190794
负责人：
Tim J Anderson
金额：
$ 50.36万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-03 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190794
关键词：
Africa Biochemical Pathway Biology Biomphalaria Brazil CRISPR/Cas technology Candidate Disease Gene Chromosome Mapping Computing Methodologies Data Drug resistance France Genes Genetic Genetic Crosses Genetic Transcription Genetic Variation Genome Genomics Genotype Helminths Heritability Human Inbreeding Individual Laboratories Larva Light Maps Measures Mediating Metabolic Pathway Methods Middle East Molecular Mutation Network-based Oman Parasites Parents Pattern Penetration Periodicity Photoperiod Population Protozoa Quantitative Trait Loci RNA Interference Resistance Rodent Sampling Schistosoma Schistosoma mansoni Schistosome Parasite Signal Pathway Snails South America Specificity Sporocysts Time Transcript Transfection Trematoda Universities Variant Virulence Water Work base candidate validation cell motility cohort exome exome sequencing experimental study genetic analysis genetic approach genetic architecture genetic linkage genetic linkage analysis genetic manipulation genome-wide improved infected vector rodent interest knock-down laboratory experiment life history mortality neglect novel trait transcriptome sequencing transmission process

项目摘要

SUMMARY Identification of the parasite genes that influence transmission, virulence and host specificity is of central interest for understanding host/parasite interactions. The central aim of this proposal is to identify the genetic basis of two such traits in Schistosoma mansoni, a parasitic fluke that infects 67 million people in South America, Middle-East and Africa. We will focus on the larval stage of the parasite lifecycle in aquatic snails. Following penetration of the snail host, schistosome larvae reproduce clonally, castrating their snail host, and hundreds to tens of thousands of motile cercariae larvae are released into the water where they infect humans or rodents. Two key transmission- related traits show high levels of heritable genetic variation among parasites. First, the timing of cercarial release from the snail varies among populations and overlaps with the water contact patterns of their vertebrate hosts. Most S. mansoni populations that primarily infect humans shed cercariae larvae in late morning, while parasite populations that primarily infect rodents shed cercariae in late afternoon or night. Late shedding has evolved at least three times in S. mansoni populations. Laboratory crosses demonstrate a simple genetic basis for this trait, but the genetic architecture of late shedding is different in the three populations where it has been documented. Second, the number of cercariae larvae shed from the intermediate aquatic snail host varies ≥7-fold among individual schistosome genotypes. High shedding parasites have greater potential for transmission but also castrate and kill their intermediate snails more rapidly than low shedding parasites. Laboratory experiments demonstrate that this trait responds rapidly to selection and is highly heritable. Schistosome parasites are unusual among parasites of humans because the complete lifecycle can be easily maintained in the laboratory, so genetic crosses can be staged and thousands of progeny isolated, while a complete genome sequence and a growing molecular toolkit now allows genomic and functional characterization. In preliminary work, we conducted genetic crosses between diurnal and nocturnal shedding parasites from Oman and identified a region on chr.1 that determines cercarial shedding time (LOD=6.1). In Aim 1, we will exploit the growing schistosome molecular toolkit to fine map and functionally analyze the gene(s) that determine shedding time in the Omani cross, and we will conduct additional crosses to determine the genetic basis of this trait in other parasite populations where late shedding is observed. In Aim 2, we will use RNAseq to examine rhythms in expression of nocturnal and diurnal shedding parasites from Oman across the 24 hr light/dark cycle, to investigate the metabolic pathways underlying control of cercarial release. Finally, in Aim 3, we will analyze genetic crosses between parasites showing 7-fold differences in numbers of cercariae shed from infected snails, and then fine map and functionally analyze the genes involved. We have previously used genetic linkage mapping and functional analysis to identify the mutations underlying oxamniquine resistance in S. mansoni. We anticipate that this approach will be equally powerful for identifying the genes that underlie heritable parasite traits that are critical for transmission, host specificity and virulence in this important human helminth parasite. Our genetic approach also provides a novel way to probe the biology of schistosome sporocysts, a neglected stage in the schistosome lifecycle that is key to understanding transmission from the snail to the vertebrate host.

概括鉴定影响传播、毒力和宿主特异性的寄生虫基因至关重要用于了解宿主/寄生虫相互作用。该提案的中心目的是确定两者的遗传基础。曼氏血吸虫（Schistosoma mansoni）具有这样的特征，这是一种寄生吸虫，感染了南美洲和中东的 6700 万人我们将重点关注水生蜗牛寄生虫生命周期的幼虫阶段。蜗牛宿主，血吸虫幼虫进行克隆繁殖，阉割其蜗牛宿主，并产生数百至数万个活动尾蚴幼虫被释放到水中，感染人类或啮齿动物有两种主要传播方式：相关性状显示寄生虫之间存在高水平的可遗传遗传变异。首先，尾蚴释放的时间。蜗牛的水接触模式因种群而异，并且与其脊椎动物宿主的水接触模式重叠。主要感染人类的曼氏沙门氏菌种群在上午晚些时候排出尾蚴幼虫，而寄生虫主要感染啮齿类动物的种群至少在下午或夜间排出尾蚴。实验室杂交证明了这一性状的简单遗传基础，但晚期脱落的遗传结构在已记录的三个种群中是不同的。从中间水生蜗牛宿主中排出的尾蚴幼虫数量在个体之间变化≥7倍高脱落寄生虫具有更大的传播潜力，但也具有阉割和杀死作用。它们的中间蜗牛比低脱落寄生虫更快。性状对选择反应迅速，并且具有高度遗传性。血吸虫寄生虫在人类寄生虫中并不常见，因为其完整的生命周期可以很容易地维持在实验室中，因此可以进行遗传杂交并分离出数千个后代，同时完整的基因组序列和不断发展的分子工具包现在可以进行基因组和功能表征。在前期工作中，我们对来自阿曼和夜间的昼夜脱落寄生虫进行了遗传杂交在 chr.1 上确定了一个决定尾蚴脱落时间的区域 (LOD=6.1)。在目标 1 中，我们将利用不断生长的血吸虫分子工具包，可对决定脱落的基因进行精细定位和功能分析在阿曼杂交中，我们将进行额外的杂交，以确定该性状在其他杂交中的遗传基础在目标 2 中，我们将使用 RNAseq 来检查观察到晚期脱落的寄生虫种群。来自阿曼的夜间和白天脱落寄生虫在 24 小时光/暗周期中的表达，以调查最后，在目标 3 中，我们将分析遗传杂交。寄生虫之间显示受感染蜗牛脱落的尾蚴数量有 7 倍的差异，然后是精细图并对相关基因进行功能分析。我们之前使用遗传连锁图谱和功能分析来识别潜在的突变我们预计这种方法对于识别曼氏沙门氏菌的耐药性同样有效。构成可遗传寄生虫特征的基因，这些特征对于传播、宿主特异性和毒力至关重要我们的遗传方法还提供了一种探索其生物学的新方法。血吸虫孢子囊，血吸虫生命周期中被忽视的阶段，是了解传播的关键从蜗牛到脊椎动物宿主。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic Crosses and Linkage Mapping in Schistosome Parasites.

DOI：
10.1016/j.pt.2018.08.001
发表时间：
2018-11
期刊：
Trends in parasitology
影响因子：
9.6
作者：
Anderson TJC;LoVerde PT;Le Clec'h W;Chevalier FD
通讯作者：
Chevalier FD

Urogenital schistosomiasis in Nigeria post receipt of the largest single praziquantel donation in Africa.

DOI：
10.1016/j.actatropica.2021.105916
发表时间：
2021-07
期刊：
Acta tropica
影响因子：
2.7
作者：
Enabulele EE;Platt RN;Adeyemi E;Agbosua E;Aisien MSO;Ajakaye OG;Ali MU;Amaechi EC;Atalabi TE;Auta T;Awosolu OB;Dagona AG;Edo-Taiwo O;Ejikeugwu CEP;Igbeneghu C;Njom VS;Orji MN;Oyinloye FOP;Ozemoka HJ;Ugah UI;Anderson TJC
通讯作者：
Anderson TJC

Prospecting for Zoonotic Pathogens by Using Targeted DNA Enrichment.

DOI：
10.3201/eid2908.221818
发表时间：
2023-08
期刊：
EMERGING INFECTIOUS DISEASES
影响因子：
11.8
作者：
Enabulele, Egie E.;Le Clec'h, Winka;Roberts, Emma K.;Thompson, Cody W.;McDonough, Molly M.;Ferguson, Adam W.;Bradley, Robert D.;Anderson, Timothy J. C.;Platt, Roy N.
通讯作者：
Platt, Roy N.

Snails, microbiomes, and schistosomes: a three-way interaction?