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: 10365369
• 负责人: Antonis Rokas
• 金额: $ 74.75万
• 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/10365369
• 关键词: Address; Animal Model; 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; Time; Untranslated RNA; Variant; Virulence; base; combat; emerging pathogen; experimental study; fungus; genetic element; genome-wide; human disease; human morbidity; human mortality; human pathogen; immunosuppressed; in vivo; innovation; insight; mortality; mouse model; novel; overexpression; pathogen; pathogenic fungus; response; 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 烟曲霉是一种主要的人类真菌病原体，每种病原体都会感染数十万人，通常导致数十万人死亡 年一些密切相关的物种也具有致病性，但引起的感染较少。相比之下，大多数其他密切 相关物种不是致病性的。病原体反复起源于非病原体，这表明， 在这个谱系中，引起疾病或致病性的能力已经独立地进化了多次。的 观察到的致病性谱不能用物种生态学的差异或确定 偏倚，表明曲霉菌致病性的重复进化至少部分具有遗传基础。 已知几个关键性状--及其潜在的基因和途径--与A. 烟曲霉的致病性，包括毒力，在人体温度下的生长，以及 次级代谢产物相比之下，令人惊讶的是，我们对细菌致病性的重复进化知之甚少。 曲霉菌和变异的特点和遗传因素，有助于其起源。是否致病 物种共享非病原体所不具备的特征和遗传元件（“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件，使其与非病原体区分开来， 亲属（“物种特异性致病性”模型）仍然未知;第三种模型，基本上是其他模型的混合 第二，也是可能的，在这种情况下，一些有助于致病性的性状和遗传元件被 保守的，有些是物种特异性的。阐明哪种模型解释了 曲霉菌致病性是开发对抗感染的策略的关键，鉴定遗传元件， 有助于毒力，并预测新的病原体出现。 这个项目将测试这些模型并推进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、在人体温度下生长和次级代谢产物产生的谱 (Aim 1）;与观察到的致病性差异相关的基因组和转录组变异（目的 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 真菌的致病性（目标3）。 该项目是创新的，因为：它将解决基本的，在很大程度上没有答案的问题，在医疗 真菌学，如真菌致病性如何演变和为什么A.烟曲霉每年感染数十万人 但它的近亲没有; B）它将产生宝贵的资源，如全面，深入 密切相关真菌谱系中关键疾病相关性状和遗传元件的变异检查 它们的致病性差异很大，这将导致产生新的，遗传上易于处理的模型， 用于研究主要真菌病原体如何起源于历史上无害的生物。