Deciphering the phenotypic and genomic traits that underlie the evolution of pathogenicity differences among Aspergillus fumigatus and its close relatives

破译烟曲霉及其近亲致病性差异进化背后的表型和基因组特征

• 批准号: 10540389
• 负责人: Antonis Rokas
• 金额: $ 69.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540389
• 关键词: Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological; Body Temperature; Chemicals; Clinical; Code; DNA; Disease; Ecology; Engineering; Environment; Evolution; Generations; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genome; Genomics; Growth; Hospitals; Human; Human body; Hybrids; In Situ; In Vitro; Infection; Link; Measures; Medical; Modeling; Nucleic Acid Regulatory Sequences; Organism; Pathogenicity; Pathway interactions; Phenotype; Phylogeny; Production; Protein Analysis; Resources; Specificity; Stress; Taxonomy; Testing; The science of Mycology; Untranslated RNA; Variant; Virulence; combat; emerging pathogen; experimental study; fungus; genetic element; genome-wide; human disease; human morbidity; human mortality; human pathogen; immunosuppressed; in vivo; innovation; insight; model organism; mortality; mouse model; novel; overexpression; pathogen; pathogenic fungus; response; secondary metabolite; stem; trait; transcriptomics

PROJECT SUMMARY Aspergillus fumigatus is a major human fungal pathogen that infects – often killing – hundreds of thousands each year. A few closely related species are also pathogenic but cause fewer infections. In contrast, most other closely related species are not pathogenic. Pathogens have originated repeatedly from non-pathogens, suggesting that the ability to cause disease or pathogenicity has evolved multiple times independently in this lineage. The observed spectrum of pathogenicity cannot be explained by differences in species' ecologies or by ascertainment bias, indicating that the repeated evolution of Aspergillus pathogenicity has, at least partially, a genetic basis. Several key traits – and their underlying genes and pathways – are known to be associated with A. fumigatus pathogenicity, including virulence, growth at the human body temperature, and the production of secondary metabolites. In contrast, we know surprisingly little about the repeated evolution of pathogenicity in Aspergillus and the variation in the traits and genetic elements that contributed to its origins. Whether pathogenic species share traits and genetic elements that are absent in non-pathogens (“conserved pathogenicity” model) or each pathogen contains a unique suite of traits and genetic elements that distinguish it from its non-pathogenic relatives (“species-specific pathogenicity” model) remains unknown; a third model, essentially a mix of the other two, is also possible, under which some traits and genetic elements that contribute to pathogenicity are conserved and some are species-specific. Elucidating which model explains the repeated evolution of Aspergillus pathogenicity is key for developing strategies to combat infections, identifying genetic elements that contribute to virulence, and predicting new pathogen emergence. This project will test these models and advance our understanding of the evolution of Aspergillus pathogenicity by investigating: the variation of species (and strains within species) that span the pathogenicity spectrum with respect to virulence, growth at the human body temperature, and secondary metabolite production (Aim 1); the genomic and transcriptomic variation associated with the observed differences in pathogenicity (Aim 2), and; how genetic elements that vary between pathogens and non-pathogens have contributed to the evolution of fungal pathogenicity (Aim 3). The project is innovative because: it will address fundamental, largely unanswered, questions in medical mycology, such as how fungal pathogenicity evolved and why A. fumigatus infects hundreds of thousands yearly but its very close relatives do not; b) it will generate invaluable resources, such as comprehensive, in-depth examinations of variation for key disease-relevant traits and genetic elements in a lineage of closely related fungi that vary extensively in their pathogenicity, and; it will lead to the generation of novel, genetically tractable model organisms for studying how major fungal pathogens originate from historically innocuous organisms.

项目总结 烟曲霉菌是一种主要的人类真菌病原体，每种真菌都会感染数十万人，通常会导致死亡。 年。一些关系密切的物种也是致病的，但造成的感染较少。相比之下，大多数其他人关系密切 近缘物种不是致病的。病原体反复来自非病原体，这表明 在这个血统中，致病或致病的能力已经独立地进化了多次。这个 观察到的致病谱不能用物种生态的差异或确定来解释 偏见，表明曲霉致病性的重复进化至少部分有遗传基础。 已知有几个关键特征及其潜在的基因和途径与A. 烟曲霉致病力，包括毒力、在人体温度下的生长和产生 次生代谢物。相比之下，我们对致病性的重复进化知之甚少。 曲霉和促成其起源的性状和遗传因素的变异。是否致病 物种共享非病原体所没有的特征和遗传元素(“保守致病性”模式) 或者，每种病原体都包含一套独特的特征和遗传元素，将其与非致病病原体区分开来 亲属(“物种特异性致病”模式)仍不清楚；第三种模式基本上是其他模式的混合体。 第二，也是可能的，在这种情况下，导致致病性的一些特征和遗传因素是 保守的，有些是物种特有的。阐明哪种模型可以解释生物的反复进化 曲霉菌的致病性是制定抗击感染策略的关键，识别 有助于毒力，并预测新病原体的出现。 这个项目将检验这些模型，并加深我们对曲霉菌进化的理解 通过调查致病性：跨越致病性的物种(和物种内的菌株)的变异 关于毒力、在人体温度下的生长和次生代谢物产生的光谱 (目标1)；与观察到的致病性差异有关的基因组和转录变异(目标1) 2)，以及病原体和非病原体之间的遗传因素如何对进化做出贡献 真菌致病性(目标3)。 该项目具有创新性是因为：它将解决基本的、基本上未得到回答的医学问题 真菌学，如真菌致病性是如何进化的，以及为什么烟曲霉每年感染数十万人 但它的近亲不会；b)它将产生宝贵的资源，如全面、深入的 亲缘关系密切的真菌谱系中与疾病相关的关键性状和遗传因素的变异检测 它们的致病力差异很大，这将导致新的、遗传上易处理的模型的产生 用于研究主要真菌病原体如何起源于历史上无害的生物的生物体。