The Genetic Basis of Virulence in Cryptococcus Neoformans

新型隐球菌毒力的遗传基础

• 批准号: 9389607
• 负责人: JOSEPH HEITMAN
• 金额: $ 38.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389607
• 关键词: Address; Affect; Alleles; Animals; Antifungal Agents; Architecture; Benign; Cells; Cessation of life; Clinical; Coculture Techniques; Communities; Complement; Complex; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cryptococcus neoformans infection; DNA; Disease; Environment; Frequencies; Fungal Drug Resistance; Genes; Genetic; Genetic Crosses; Genetic Determinism; Genetic Population Study; Genetic Recombination; Genome; Genomics; Genotype; Geographic Distribution; Geographic Locations; High temperature of physical object; Individual; Infection; Knowledge; Lead; Metabolic; Molecular; Morphology; Online Systems; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Physiological; Polysaccharides; Population; Population Heterogeneity; Prevention; Prevention strategy; Property; Public Health; Quantitative Trait Loci; Research; Research Personnel; Resources; Sampling; Source; Statistical Models; Surveys; Techniques; Variant; Virulence; Virulent; Yeasts; analytical tool; capsule; design; gene replacement; genetic linkage analysis; genome sequencing; genome wide association study; macrophage; offspring; pathogen; prevent; public health relevance; success; trait; whole genome

Project Summary The fungal pathogen Cryptococcus neoformans is estimated to cause disease in more than 1,000,000 people worldwide every year, resulting in greater than 600,000 deaths. However, not all Cryptococcus isolates cause lethal infections; some are relatively benign while others are hypervir- ulent. Differences in pathogenicity are often correlated with variation in specific morphological and physiological features such as the ability to grow at high temperatures, the size of the pro- tective polysaccharide capsule surrounding the yeast cell, or resistance to antifungal drugs. In order to develop better ways to prevent and treat cryptococcal disease we need to understand the underlying genetic differences that lead to changes in virulence and virulence-related traits. We also need to understand the frequency and distribution of these genetic differences in different parts of the world. To tackle these problems, the proposed research will use a combination of experimental and statistical approaches to dissect the causal genetic basis of variation in virulence and virulence- related traits. In Aim 1 we will employ a statistical technique called Quantitative Trait Locus (QTL) mapping, that exploits genotypic and phenotypic differences among offspring derived from genetic crosses to identify regions of the genome (loci) and DNA changes (alleles) that con- tribute to differences in virulence traits. We will validate the contributions of the loci identified in this manner using gene replacements and related techniques. In Aim 2 we will subject ge- netically diverse populations of Cryptococcus to selection in animal hosts. Following selection, pooled whole genome sequencing will be used to identify loci and alleles that are favored during infection. This technique provides an unbiased approach for discovering loci that contribute to virulence, and will both complement and extend the results of Aim 1. In Aim 3 we will frame our findings in the context of natural populations of Cryptococcus by studying the frequency and geo- graphic distributions of virulence alleles identified in Aims 1 and 2. This aim will employ a large, global sample of Cryptococcus strains isolated from both clinical settings and the natural environ- ment. This information will be used to carry out Genome-Wide Association (GWAS) mapping of virulence traits and to identify regions of the world where there are higher frequencies of virulent genotypes or where there is potential for increased virulence through recombination.

项目摘要 据估计，真菌病原体的加密型新形象球会导致疾病超过 每年在全球100万人，导致60万人死亡。但是，不是全部 加密环球株引起致命感染；有些是相对良性的，而另一些则是hypervir- Ulent。致病性差异通常与特定形态的变化相关 和物理特征，例如在高温下生长的能力 围绕酵母细胞或抗真菌药物的抗多糖胶囊。 为了开发更好的方法来预防和治疗隐球菌疾病，我们需要了解 导致病毒和病毒相关性状变化的基本遗传差异。我们 还需要了解这些遗传差异在不同的频率和分布 世界各地。 为了解决这些问题，拟议的研究将结合实验和 阐述病毒和病毒变异的因果遗传基础的统计方法 相关特征。在AIM 1中，我们将采用一种称为定量性状基因座的统计技术 （QTL）映射，利用了衍生的后代的基因型和表型差异 从遗传杂交到识别基因组（基因座）和DNA变化（等位基因）的区域 致敬病毒特征的差异。我们将验证当地身份证明的贡献 在AIM 2中，我们将进行ge- 在动物宿主中选择的网络群体的网络多样性种群。以下选择， 汇总的整个基因组测序将用于识别在局部和等位基因期间受到青睐的局部和等位基因 感染。该技术为发现有助于的基因座提供了一种公正的方法 病毒，并将完成并扩展AIM 1的结果。在AIM 3中，我们将构架我们的 通过研究频率和地理 目标1和2中鉴定出的病毒等位基因的图形分布。此目标将采用大型， 从临床环境和自然环境中分离出的加密环球菌株的全球样本 - 精神。此信息将用于进行全基因组关联（GWAS）映射 病毒特征并确定病毒频率较高的世界地区 基因型或通过重组有可能增加病毒的地方。