Genetics and genomics of schistosome resistance in snails

蜗牛血吸虫抗性的遗传学和基因组学

• 批准号: 10649654
• 负责人: SI-MING ZHANG
• 金额: $ 54.92万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-17 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649654
• 关键词: Address; Adolescent; Adult; Advocate; Affect; Alleles; Area; Attention; Biomphalaria; Brazil; Breeding; Bulinus; CRISPR interference; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Competence; Coupled; Data; Development; Foundations; Fresh Water; Generations; Genes; Genetic; Genetic Recombination; Genetic Variation; Genetic study; Genitourinary system; Genome; Genomic Segment; Genomic approach; Genomics; Human; Immunobiology; Immunologics; Inbreeding; Individual; Infection; International; Intervention; Intestines; Knock-out; Knowledge; Laboratory Finding; Maps; Methods; Modeling; Modernization; Molecular; Parents; Persons; Phenotype; Population; Poverty Areas; Predisposition; Quantitative Trait Loci; RNA Interference; RNA analysis; Reporting; Resistance; Resolution; Role; Scanning; Schistosoma; Schistosoma haematobium; Schistosoma mansoni; Schistosome Parasite; Schistosomiasis; Single Nucleotide Polymorphism; Snails; System; Technology; Testing; Variant; comparative; comparative genomics; constitutive expression; cost effective; differential expression; disease transmission; functional genomics; genetic analysis; genetic approach; genetic resistance; genetic resource; genome editing; genome resource; genome sequencing; genome-wide; insight; knock-down; neglected tropical diseases; novel; programs; public health relevance; resistance gene; response; success; tool; transcriptome sequencing; transcriptomics; transmission blocking; transmission process; vector; whole genome

SUMMARY Transmission of human schistosome parasites depends on availability of suitable aquatic snail intermediate hosts. If no schistosome-transmitting snails are present, or snails no longer support schistosome development, there will be no schistosomiasis. Developing snail-targeted genetic control programs has long been advocated, but hampered by the lack of necessary genetic knowledge and effective germline manipulation tools. The objective of this project is to exploit our recently developed genetic and genomic resources, in combination with application of emerging powerful technologies, to address fundamental mechanisms of schistosome resistance of snails in two snail-schistosome systems, Biomphalaria spp.–Schistosoma mansoni and Bulinus spp.–S. haematobium, which are involved in transmission of intestinal and urogenital schistosomiasis, respectively. The two snail-schistosome systems are responsible for approximately 99% of human schistosomiasis transmission in the world. We propose to employ two new snail models, Bi. glabrata– S. mansoni and Bu. truncatus–S. haematobium to represent the two systems for the study. In Aim 1, we will apply whole genome sequencing (WGS) to scan single nucleotide polymorphisms (SNPs) of individual recombination inbred lines (RILs) to generate high-resolution genetic maps of schistosome resistance in juvenile and adult Bi. glabrata, the best-studied snail model of schistosomiasis. The RILs have been bred from our new model that consists of two homozygous lines of Bi. glabrata, one fully susceptible to, and the other completely resistant to, S. mansoni, the most important causative agent of intestinal schistosomiasis. In Aim 2, we will employ RNA sequencing (RNAseq) to investigate differential expression and allelic variation of genome-wide genes using our newly developed genetic resources (i.e., RIL snails and their two homozygous parent snails). A comprehensive analysis of RNAseq data coupled with genes identified in the fine resistance loci will lead to accurate identification of small number of resistance candidates, which will be used for subsequent studies, including genetic variation of resistance genes in natural populations in endemic areas proposed in this aim. In Aim 3, we will use a combined approach of functional and comparative genomics to identify syntenic regions between Bi. glabrata and Bu. truncatus and reveal the genomic basis of schistosome resistance in Bu. truncatus, an intermediate host of S. haematobium. Paradoxically, S. haematobium, despite being the most abundant of all schistosome species infecting people, has received very little attention with respect to its interactions with its bulinid snail hosts. In Aim 4, we will utilize RNAi (RNA interference) and CRISPR (clustered regularly interspaced short palindromic repeats) to functionally verify the candidate genes affecting snail compatibility to S. mansoni or S. haematobium. This study will lead to a much deeper understanding of schistosome resistance in Bi. glabrata, provide the first molecular insight into the genomic basis underpinning competence of bulinid snails to schistosome, and help develop more effective and novel methods for controlling schistosomiasis.

总结 人类寄生虫的传播取决于是否有合适的水生蜗牛 中间宿主如果不存在传播寄生虫的蜗牛，或者蜗牛不再支持寄生虫， 发展，就不会有血吸虫病。开发针对蜗牛的遗传控制项目已经很久了， 一直提倡，但由于缺乏必要的遗传知识和有效的生殖系操作， 工具.该项目的目标是利用我们最近开发的遗传和基因组资源， 结合新兴的强大技术的应用，以解决 双脐螺-曼氏血吸虫两种螺体系统中螺体的抗性 和泡螺（Bulinus spp.）嗜血杆菌，参与肠道和泌尿生殖道的传播 血吸虫病，分别。这两个蜗牛-血吸虫系统负责大约99%的 人类血吸虫病在世界范围内传播。我们建议采用两个新的蜗牛模型，Bi。光滑的，光滑的 S. mansoni和Bu.截形S.以代表研究的两个系统。在目标1中，我们 应用全基因组测序（WGS）技术扫描个体的单核苷酸多态性（SNP）， 重组自交系（RILs），以生成高分辨率的青少年抗蚜基因图谱 成人Bi glabrata，血吸虫病研究最好的蜗牛模型。RIL是从我们的新品种中培育出来的 该模型由两个纯合的Bi系组成。光滑，一个完全敏感，另一个完全敏感， 抗性，S.曼氏血吸虫病是肠道血吸虫病最重要的病原体。在目标2中，我们将 利用RNA测序（RNAseq）研究全基因组的差异表达和等位基因变异， 基因使用我们新开发的遗传资源（即，RIL蜗牛和它们的两个纯合亲本蜗牛）。 RNAseq数据的综合分析加上在精细抗性基因座中鉴定的基因将导致 准确鉴定少量耐药候选物，用于后续研究， 包括为此目的提出的流行区自然群体中抗性基因的遗传变异。在 目的3，我们将使用功能基因组学和比较基因组学相结合的方法来鉴定同线区域 在Bi之间。glabrata和Bu. truncatus的研究，揭示了Bu.截形， 是S.埃及血吸虫巧合的是，S。尽管是最丰富的 所有感染人类的有害物种，很少有人关注它与其 Bulinid snail寄主。在目标4中，我们将利用RNAi（RNA干扰）和CRISPR（定期聚类）， 间隔的短回文重复序列），以在功能上验证影响蜗牛相容性的候选基因， S. mansoni或S.埃及血吸虫这项研究将导致更深入地了解细菌耐药性 在Bi。glabrata，提供了第一个分子洞察到的基因组基础支撑能力的bulinid 研究人员说，他们的研究有助于开发更有效和新的方法来控制血吸虫病。