The evolution of virulence in the fungal pathogen Histoplasma

真菌病原体组织胞浆菌毒力的进化

• 批准号: 10549333
• 负责人: Daniel Matute
• 金额: $ 63.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-17 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549333
• 关键词: Affect; Alleles; Animal Model; Biological Assay; Biological Models; Cell Culture Techniques; Cessation of life; Clinical; Clinical Data; Collection; Communities; Data; Disease; Evolution; Exposure to; Frequencies; Funding Opportunities; Future; Gene Exchanges; Genes; Genetic; Genetic Models; Genome; Genomics; Geographic Locations; Goals; HIV Seropositivity; Haploidy; Health; Histoplasma; Histoplasmosis; Hospitalization; Human; Immune response; In Vitro; Infection; Kinetics; Laboratory Study; Life; Lung; Lung diseases; Lung infections; Macrophage; Maps; Medical; Methods; Modeling; Molecular Genetics; Mus; Natural Selections; Organism; Outcome; Pathogenesis; Pathogenicity; Patient-Focused Outcomes; Patients; Pattern; Persons; Phase; Phenotype; Phylogenetic Analysis; Population; Population Genetics; Portraits; Process; Proliferating; Research; Research Support; Resources; Role; Sample Size; Sampling; Structure; System; Testing; The science of Mycology; Time; Travel; United States; United States National Institutes of Health; Variant; Virulence; Virulence Factors; Yeasts; burden of illness; candidate validation; climate change; experimental study; fitness; functional genomics; fungal genetics; fungus; genetic approach; genetic manipulation; genetic variant; genome wide association study; genome-wide; genomic tools; human pathogen; in vivo; interest; microbial; negative affect; pathogen; pathogenic fungus; programs; response; sample collection; tool; trait; transmission process; virulence gene; web portal

ABSTRACT/PROJECT SUMMARY Background: Histoplasma is a pathogenic fungus that causes life-threatening lung infections. About 500,000 people are exposed to Histoplasma each year in the United States, and over 60% of the US population has been exposed to the fungus at some point in their life. We have shown that Histoplasma is composed of at least five different species that vary considerably in the type and magnitude of disease they cause. Broad, long-term objective: The proposed research will help us identify the genes that allow virulence to emerge and spread, as well as develop a panel of isolates that once deep-sequenced can be used by the community of medical mycologists to map any trait of interest in Histoplasma. The objective of this proposal is to discover whether the genes responsible for differences in virulence among isolates are similar across species. Specific aims: Aim 1 of the study proposes to generate genetic reference panels for three species of the human pathogen Histoplasma. We will use this resource to identify alleles involved with virulence differences within and between species. Aim 2 will genetically test the phenotypic effects (i.e., virulence in vitro and in vivo) of the genomic hypotheses produced in Aim1. Aim 3 will study the spread of alleles in clinical samples over a period of 40 years and will integrate the results from Aims 1 and 2, allowing us to determine whether any of the alleles involved in virulence have increased in frequency. Method: This haploid organism is ideal for the laboratory study of fungal pathogens, and it is well-suited for genomic analysis. We will generate genetic reference panels for three different species of Histoplasma with state-of-the-art genomic tools and genome-wide association mapping. We will use this panel to identify the genetic basis of virulence differences within isolates of the same species. Notably, we will generate an online portal to analyze GWAS data, a first in the medical mycology community. Preliminary results show that given the amount of phenotypic variance in virulence, our approach and proposed sample sizes make this project feasible. Validation of candidate virulence genes will be undertaken according to established cell culture and mouse infection assays. Our approach will generate tools and reference panels for the fungal genetics community. Health-relatedness: The disease burden caused by Histoplasma species is substantial in the United States, with a conservative estimate of at least 3.4 cases per 100,000 population. If infectious strains can transmit the ability to cause infection to less harmful strains through gene exchange, the potential future disease burden will grow as global trade, travel and climate change bring new species of the fungus into overlapping geographic regions. The proposed research will identify what loci are involved in the evolution of virulence and will study the influence of natural selection in their evolution in recent timescales. This application is in response to a recent NIH Funding Opportunity Announcement (PA-19-082) supporting research on histoplasmosis and two other endemic fungal diseases, and this program specifically encourages submission of R01 applications that will “expand understanding of speciation and impact on clinical outcome.”

摘要/项目摘要 背景：组织肿瘤是一种致病的真菌，会导致威胁生命的肺部感染。约500,000 在美国，人们每年都会暴露于组织中，美国超过60％的人口 我们已经表明，组织肿瘤由AT组成 在它们引起的疾病的类型和大小中，至少有五种不同的物种。 广泛的长期目标：拟议的研究将帮助我们确定允许病毒的基因 出现和传播，以及开发一个隔离株，一旦深入序列可以由 医学真菌学家社区绘制组织浮肿的任何感兴趣的特征。该提议的目的是 发现造成分离株病毒差异的基因是否相似 物种。 具体目的：研究1的目标提案，以生成三种物种的遗传参考面板 人病原体组织肿瘤。我们将使用此资源来识别与病毒差异有关的等位基因 物种之间和之间。 AIM 2将在遗传上测试表型效应（即体外毒力和体内毒力） AIM1中产生的基因组假设。 AIM 3将研究等位基因在临床样本中的传播 期限为40年，将整合目标1和2的结果，使我们能够确定是否有任何 参与病毒的等位基因的频率增加。 方法：这种单倍体生物是真菌病原体实验室研究的理想选择，非常适合 基因组分析。我们将为三种不同种类的组织质量生成遗传参考面板 最先进的基因组工具和全基因组关联映射。我们将使用此面板来识别 同一物种分离株内病毒差异的遗传基础。值得注意的是，我们将在线生成 门户网站分析GWAS数据，这是医学真菌学社区的第一个。初步结果表明给定 病毒表型差异的量，我们的方法和建议的样本量使该项目 可行的。候选病毒基因的验证将根据已建立的细胞培养和 小鼠感染评估。我们的方法将为真菌遗传学生成工具和参考面板 社区。 与健康相关：由组织肿瘤引起的伯恩在美国很大， 保守估计为每10万人人口至少3.4例。如果传染性菌株可以传播 通过基因交换引起感染较小的有害菌株的能力，潜在的未来疾病伯恩将 随着全球贸易，旅行和气候变化的成长，将新真菌的新物种带入重叠的地理 地区。拟议的研究将确定局部与病毒进化有关的局部性，并将研究 自然选择在最近的时间尺度演变中的影响。此应用程序是对 NIH的最新资助机会公告（PA-19-082）支持组织质症研究和两项研究 其他内在真菌疾病，该程序专门鼓励提交R01应用程序 将“扩大对规范的理解和对临床结果的影响”。