Virulence genes in recombinant strains of Toxoplasma

描述(申请人提供)：这项建议旨在确定弓形虫重组克隆的急性毒力的遗传基础。大多数弓形虫分离株属于三种克隆性“类型”之一，在小鼠身上具有不同的疾病结果。感染一种I型生物是致命的，而小鼠在接种II型或III型生物时存活1000倍。值得注意的是，由II型和III型菌株之间的基因重组产生的弓形虫克隆(称为S23)的毒力是亲本的1000倍，这表明来自无毒菌株的基因座可以相互作用，产生毒力表型。我会仔细分析这出乎意料的，但是 流行病学上重要的是，通过识别导致克隆S23表型的等位基因进行观察。在建立了基于S23特异性宿主细胞对感染的反应的弓形虫毒力体外相关性后，我将S23与其无毒亲本进行回交，并利用数量性状基因座(QTL)定位与毒力相关的基因组片段。然后，进行S23不同无毒亲本之间的等位基因交换，以确定致病等位基因本身。这项工作将加深我们对弓形虫在实验室和现场条件下毒力进化的理解。

DESCRIPTION (provided by applicant): This proposal aims to determine the genetic basis of acute virulence in a recombinant clone of the parasite Toxoplasma gondii. Most T. gondii isolates belong to one of three clonal "Types" with distinct disease outcomes in mice. Infection with a single Type I organism is lethal, while mice survive 1000-fold higher inoculations of Type II or III. Remarkably, a T. gondii clone (called S23) resulting from genetic recombination between type II and III strains is 1000 times more virulent than either parent, showing that loci from avirulent strains can interact to produce virulent phenotypes. I will dissect this unexpected, but epidemiologically important, observation by identifying the alleles responsible for the phenotype of clone S23. After developing an in vitro correlate for T. gondii virulence based on S23-specific host cell responses to infection, I will conduct backcrosses of S23 to its avirulent parents, and use quantitative trait loci (QTL) mapping to identify genomic segments linked virulence. Then, I will carry out allele exchanges between the avirulent parents of clone S23 different to identify the virulence alleles themselves. This work will improve our understanding of the evolution of T. gondii virulence under both laboratory and field conditions.