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：组织胞浆菌是一种致病真菌，可引起危及生命的肺部感染。约50万 在美国，每年都有人接触组织胞浆菌，超过 60% 的美国人曾接触过组织胞浆菌 在他们生命中的某个时刻接触过真菌。我们已经证明组织胞浆菌是由 至少有五种不同的物种，它们引起的疾病的类型和严重程度差异很大。 广泛的长期目标：拟议的研究将帮助我们识别允许毒力传播的基因 的出现和传播，以及开发一组分离物，一旦深度测序就可以被 医学真菌学家社区绘制组织胞浆菌任何感兴趣的特征。该提案的目标是 发现导致分离株毒力差异的基因在不同菌株之间是否相似 物种。 具体目标：该研究的目标 1 提出为三个物种生成遗传参考面板。 人类病原体组织胞浆菌。我们将使用此资源来识别与毒力差异相关的等位基因 物种内部和物种之间。目标 2 将从基因角度测试表型效应（即体外和体内毒力） Aim1 中产生的基因组假设。目标 3 将研究等位基因在临床样本中的传播情况 为期 40 年，并将整合目标 1 和 2 的结果，使我们能够确定是否存在任何 涉及毒力的等位基因频率有所增加。 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，并且非常适合 基因组分析。我们将为三种不同种类的组织胞浆菌生成遗传参考面板 最先进的基因组工具和全基因组关联图谱。我们将使用此面板来识别 同一物种分离株内毒力差异的遗传基础。值得注意的是，我们将生成一个在线 分析 GWAS 数据的门户，这在医学真菌学界尚属首例。初步结果表明，给定 毒力的表型变异量、我们的方法和建议的样本量使这个项目 可行的。候选毒力基因的验证将根据已建立的细胞培养物和 小鼠感染测定。我们的方法将为真菌遗传学生成工具和参考面板 社区。 健康相关性：在美国，由组织胞浆菌引起的疾病负担是巨大的， 保守估计每 10 万人中至少有 3.4 例病例。如果传染性菌株可以传播 通过基因交换引起危害较小的菌株感染的能力，未来潜在的疾病负担将 随着全球贸易、旅行和气候变化将新的真菌物种带入重叠的地理区域，这种真菌的数量也在不断增长 地区。拟议的研究将确定哪些位点参与毒力的进化，并将研究 自然选择对其近代进化的影响。此应用程序是为了响应 最近的 NIH 资助机会公告 (PA-19-082) 支持组织胞浆菌病和两项研究 其他地方性真菌病，该计划特别鼓励提交符合以下条件的 R01 申请： 将“扩大对物种形成及其对临床结果影响的理解。”