The Genetic Basis of Virulence in Cryptococcus Neoformans

新型隐球菌毒力的遗传基础

• 批准号: 10188404
• 负责人: JOSEPH HEITMAN
• 金额: $ 47.72万
• 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 2023-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188404
• 关键词: Address; Affect; Alleles; Animals; Antifungal Agents; Benign; Cells; Cessation of life; Clinical; Coculture Techniques; Communities; Complement; Complex; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; 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 architecture; genetic linkage analysis; genome sequencing; genome wide association study; genomic locus; macrophage; offspring; pathogen; pathogenic fungus; 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.

项目总结