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.

项目摘要 曲霉富马图斯是一种主要的人类真菌病原体，被感染（常常杀死）数十万个 年。一些密切相关的物种也具有致病性，但引起更少的感染。相反，大多数其他密切 相关物种不是致病性的。病原体已反复起源于非公主，表明 在该血统中，引起疾病或致病性的能力已独立地发展。 观察到的致病性光谱不能通过物种生态学的差异或确定性来解释 偏见，表明曲绿曲霉致病性的反复演变至少部分是遗传基础。 已知几个关键特征及其基本基因和途径与A有关。 富马图斯致病性，包括病毒，人体温度下的生长以及产生 次生代谢产物。相比之下，我们对致病性反复演变的不满意 曲曲霉及其造成其起源的性状和遗传因素的变化。是否致病 物种具有非宣传原理中缺乏的特征和遗传因素（“保守的致病性”模型） 或每种病原体都包含独特的特征和遗传因素，可将其与非致病性区分开 亲戚（“物种特异性致病性”模型）仍然未知；第三个模型，本质上是另一个模型 第二，也是可能的，在这些特征和有助于致病性的遗传因素是 保守，有些是特定于规格的。阐明哪种模型解释了重复的演变 曲霉的致病性是制定抗击感染的策略的关键，确定遗传因素 有助于病毒，并预测新的病原体出现。 该项目将测试这些模型，并提高我们对曲霉的演变的理解 通过研究：跨越致病性的物种（物种中的菌株）的变化（物种中的菌株） 关于病毒，人体温度的生长和继发代谢产生的频谱 （目标1）;与观察到的致病性差异相关的基因组和转录组变异（AIM 2），;病原体和非历史雄激素之间如何变化的遗传因素如何促进进化 真菌致病性（AIM 3）。 该项目具有创新性，因为：它将解决医疗中的基本问题，在很大程度上没有解决的问题 真菌学，例如真菌致病性如何发展 但是它的亲戚没有。 b）它将产生宝贵的资源，例如全面，深入 与密切相关真菌谱系中关键疾病相关性状和遗传因素的差异的考试 这在其致病性上有很大不同，并且；它将导致新颖的，一般可牵引的模型 研究主要真菌病原体是如何起源于历史上无害生物的生物。