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Evolutionary multispecies transcriptomics to reveal genes that govern fungal spore germination and pathogenesis

进化多物种转录组学揭示控制真菌孢子萌发和发病机制的基因

基本信息

批准号：
10612374
负责人：
Anita Sil
金额：
$ 73.37万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612374
关键词：
Aspergillus fumigatus Aspergillus nidulans Biological Assay Biology Candidate Disease Gene Chaetomium Coccidioides Coccidioides posadasii Data Development Developmental Biology Diagnostic Disease Disease Progression Disparate Environment Event Evolution Fungal Genes Fungal Genome Fungal Spores Fungal Vaccines Fusarium Gene Expression Genes Genomics Germination Goals Growth Histoplasma Histoplasma capsulatum Human Infection Intervention Knock-out Knowledge Macrophage Mammals Modeling Mycoses Neurospora crassa Organism Pathogenesis Pathogenicity Pattern Phenotype Phylogenetic Analysis Plants Publications Publishing Reproduction spores Research Role Sexual Development Technology Temperature Time Vaccines Work comparative comparative genomics diagnostic tool dimorphism experimental study fungus gene function host colonization human pathogen innovation interest knockout gene novel diagnostics opportunistic pathogen pathogen pathogenic fungus prophylactic trait transcriptome sequencing transcriptomics vector-borne

项目摘要

Project Summary Fungal pathogens of humans are prevalent in the environment, and commonly come into contact with hosts via dispersal of vegetative spores. Although spore germination and subsequent development are recognized as critical to the initiation of fungal-host interactions, little is known about the fungal genes that govern these events. Our goal is to leverage comparative genomics, evolutionary biology and fungal pathogenesis to define genes that are essential for spore germination, subsequent growth, and host colonization in an evolutionarily diverse group of fungi. We have chosen fungi with a range of abilities to cause disease upon interaction of spores with mammalian hosts, including primary, opportunistic, and nonpathogenic species. We will take advantage of a highly effective and innovative pipeline that reveals genes whose evolving roles have led to phenotypic differences among these species. PIs Trail and Townsend have defined a paradigm that brings together comparative genomics, developmental biology, and transcriptomics into a single, unified phylogenetic framework that will identify key genes that govern spore germination and outgrowth in these fungi. The linchpin of our approach is use of the evolutionary relationship between the fungi to infer genes whose expression has been altered during evolution from their ancestral state to each present-day lineage, thus allowing specific traits (such as pathogenesis) to evolve. In our recently published work and preliminary data, this approach was immensely powerful for identifying genes whose evolving role led to developmental and phenotypic differences among species during (1) fungal sexual development and (2) spore germination and early infection during fungal pathogenesis of plants. We will use a common medium to germinate spores from the following fungi: the primary pathogens Histoplasma capsulatum and Coccidioides posadasii, the opportunistic pathogens Aspergillus fumigatus, Fusarium oxysporum, and Chaetomium elatum, the infrequent opportunistic pathogen Aspergillus nidulans, and the non-pathogenic Neurospora crassa. We will subject these fungi to transcriptomics over a time-course of germination and subsequent development under temperature conditions relevant to germination in the environment vs. in a mammalian host. We will reconstruct evolutionary changes of gene expression across these multiple species to identify genes that have undergone recent shifts in gene expression, in particular shifts that occurred along the shared ancestral branches where key traits (such as the ability to colonize mammals) have evolved. These experiments will yield a high-confidence set of candidate genes whose function is expected to be critical for spore germination and development in each organism. We will use gene knock-out technology to interrogate the function of these candidate genes in spore germination and development. These studies will identify potential targets for diagnostic, prophylactic, and vaccine interventions for ubiquitous fungal infections of humans.

项目摘要人类的真菌病原体在环境中普遍存在，并且通常与宿主接触通过营养孢子的传播。虽然孢子萌发和随后的发育被认为是对于真菌-宿主相互作用的启动至关重要，但对控制这些事件的真菌基因知之甚少。我们的目标是利用比较基因组学、进化生物学和真菌致病机理来定义基因这是必不可少的孢子萌发，随后的增长，并在一个进化多样的宿主殖民真菌群。我们已经选择了具有一系列在孢子与真菌相互作用时引起疾病的能力的真菌。哺乳动物宿主，包括原发性、机会性和非致病性物种。我们将利用一个一个高效和创新的管道，揭示了基因的演变作用，导致表型这些物种之间的差异。PI Trail和汤森定义了一种范式，比较基因组学、发育生物学和转录组学整合为一个统一的系统发育框架这将确定这些真菌中控制孢子萌发和生长的关键基因。我们的关键一种方法是利用真菌之间的进化关系来推断基因的表达已经在从祖先状态进化到现在的每一个血统的过程中发生了变化，从而允许特定的特征（如作为发病机制）来进化。在我们最近发表的工作和初步数据中，这种方法非常有效。强大的识别基因，其演变的作用导致发展和表型差异之间在（1）真菌性发育和（2）孢子萌发和早期感染的真菌植物的致病机理我们将使用一个共同的培养基来发芽孢子从以下真菌：主要病原体荚膜组织胞浆菌和波氏球孢子菌，条件致病菌烟曲霉，尖孢镰刀菌（Fusarium oxysporum）和高毛壳菌（Chaetomium elatum），罕见的机会致病菌构巢曲霉（Aspergillus nidulans），以及非致病性粗糙脉孢菌我们将这些真菌进行转录组学研究，在与种子萌发相关的温度条件下的萌发和随后的发育环境中与哺乳动物宿主中。我们将重建这些基因表达的进化变化，多个物种，以确定基因表达发生了最近的变化，特别是变化，发生在沿着共同的祖先分支，在那里关键特征（如殖民哺乳动物的能力）进化了这些实验将产生一组高置信度的候选基因，其功能预计将对每种生物的孢子萌发和发育至关重要。我们将使用基因敲除技术，探讨这些候选基因在孢子萌发和发育中的功能。这些研究将确定普遍存在的真菌感染的诊断、预防和疫苗干预的潜在靶点，人类