Comparative and functional genomics of Toxoplasma and Hammondia hammondi

弓形虫和 Hammondia hammondi 的比较和功能基因组学

基本信息

  • 批准号:
    9090012
  • 负责人:
  • 金额:
    $ 35.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-15 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Toxoplasma gondii is an important opportunistic pathogen of humans where it can cause severe disease in the developing fetus, immunocompromised individuals, and in certain cases healthy adults. In contrast the nearest extant relative of T. gondii, Hammondia hammondi, does not infect humans and is highly avirulent in mice, and experimental infections are characterized by rapid conversion to "terminally differentiated" cyst stages. These in vivo virulence differences are recapitulated in vitro, where H. hammondi spontaneously converts into a terminally differentiated cyst stage. We have extensive published and unpublished preliminary data demonstrating that T. gondii and H. hammondi share >99% of their genes in nearly perfect synteny, and that the T. gondii and H. hammondi transcriptomes during development are similar but have key differences in the transcription of multiple candidate virulence effectors and transcription factors. In the work outlined in this 3 year R01 proposal we use the T. gondii/H. hammondi system to identify the gene regulatory mechanisms that drive T. gondii pathogenesis, with a particular focus on bradyzoite cyst stages that are the leading cause of severe toxoplasmosis in HIV/AIDS and transplant patients. In Aim 1 we use ultra-deep, strand-specific RNAseq at time points that encompass clear developmental transitions during in vitro growth to identify genes and genetic networks that regulated in a species-specific manner. In doing so we will identify 1) putative secreted virulence effectors and 2) transcription factors that are uniquely expressed in one species over the other. We will then determine their role in T. gondii biology using gene deletion and cross-species complementation experiments. Success of this Aim is facilitated by extensive published and preliminary data comparing the genomes, in vitro growth rates, transcription profiles, and host responses to T. gondii and H. hammondi. In Aim 2 we address the role of the host in species-specific growth phenotypes. To do this we will compare 1) infection dynamics of T. gondii and H. hammondi in vivo using parallel histological assays to identify differences in the cellular and humoral immune response and 2) the overall infectivity and virulence of H. hammondi in innate-immune deficient mouse strains that are highly susceptible to T. gondii infection. Through these studies we will identify new T. gondii secreted effectors and transcription factors that underlie the dramatic phenotypic differences between these species, and how these effectors might impact the host response to infection. These studies should also more broadly impact our understanding of how, on a gene- by-gene basis, virulent pathogens emerge from comparatively avirulent phenotypic backgrounds.
 描述(申请人提供):弓形虫是一种重要的人类条件致病菌,它可以在发育中的胎儿、免疫功能受损的人以及某些情况下健康的成年人中导致严重疾病。相比之下,与弓形虫现存最接近的近亲Hammondia hammondi不会感染人类,对小鼠具有高度的毒性,实验性感染的特点是迅速转变为“终末分化”的包囊阶段。这些体内毒力差异在体外被概括,哈蒙迪杆菌自发地转化为终末分化的包囊阶段。我们有大量已发表和未发表的初步数据表明,弓形虫和哈蒙迪疟原虫99%的基因几乎完全一致,而且弓形虫和哈蒙迪疟原虫在发育过程中的转录本相似,但在多个候选毒力效应因子和转录因子的转录方面存在关键差异。在这份为期3年的R01提案中概述的工作中,我们使用弓形虫/H.Hammondi系统来识别驱动弓形虫致病的基因调控机制,特别关注缓殖体包囊阶段,这是导致艾滋病毒/艾滋病和移植患者严重弓形虫病的主要原因。在目标1中,我们在体外生长过程中包含明显发育转变的时间点上使用超深、链特异的RNAseq来识别以物种特有的方式调节的基因和遗传网络。在此过程中,我们将确定1)假定的分泌型毒力效应因子和2)转录因子,它们在一个物种中比在另一个物种中唯一表达。然后,我们将通过基因缺失和跨物种互补实验来确定它们在弓形虫生物学中的作用。这一目标的成功是由大量已发表的初步数据促进的,这些数据比较了弓形虫和汉蒙迪的基因组、体外生长速度、转录图谱和宿主反应。在目标2中,我们讨论了寄主在物种特定生长表型中的作用。为此,我们将1)比较弓形虫和汉蒙地弓形虫在体内的感染动态,使用平行的组织学检测来确定不同的 细胞和体液免疫反应和2)哈蒙迪对弓形虫感染高度敏感的先天免疫缺陷小鼠品系的总体感染性和毒力。通过这些研究,我们将识别新的弓形虫分泌的效应物和转录因子,这些效应物和转录因子是这些物种之间巨大表型差异的基础,以及这些效应物可能如何影响宿主对感染的反应。这些研究还应该更广泛地影响我们对在逐个基因的基础上如何从相对无毒的表型背景中出现毒力病原体的理解。

项目成果

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JON P BOYLE其他文献

JON P BOYLE的其他文献

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{{ truncateString('JON P BOYLE', 18)}}的其他基金

Placental resistance and response to the teratogenic pathogen Toxoplasma gondii
胎盘对致畸病原体弓形虫的抵抗力和反应
  • 批准号:
    10453973
  • 财政年份:
    2022
  • 资助金额:
    $ 35.73万
  • 项目类别:
Placental resistance and response to the teratogenic pathogen Toxoplasma gondii
胎盘对致畸病原体弓形虫的抵抗力和反应
  • 批准号:
    10600051
  • 财政年份:
    2022
  • 资助金额:
    $ 35.73万
  • 项目类别:
Finishing multiple genomes in EupathDB using Oxford Nanopore Single Molecule sequencing
使用 Oxford Nanopore 单分子测序在 EupathDB 中完成多个基因组
  • 批准号:
    10188420
  • 财政年份:
    2020
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    10750395
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    10461884
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    10267775
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    10772454
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    10669739
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    9282262
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:
Comparative and functional genomics of Toxoplasma and Hammondia hammondi
弓形虫和 Hammondia hammondi 的比较和功能基因组学
  • 批准号:
    8861405
  • 财政年份:
    2015
  • 资助金额:
    $ 35.73万
  • 项目类别:

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