Genetics of fungal persistence and pathogenicity in mammalian hosts

哺乳动物宿主中真菌持久性和致病性的遗传学

基本信息

批准号：
10874018
负责人：
Ian Michael Ehrenreich
金额：
$ 62.4万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10874018
关键词：
Adhesions Affect Alleles Antifungal Therapy Bar Codes Blood - brain barrier anatomy Body Temperature Brain CRISPR/Cas technology Candida albicans Candidate Disease Gene Cells Chromosome Mapping Clinical Cloning Cre-LoxP Data Development Diploidy Dissection Gene Expression Genes Genetic Genotype Haploidy Health Benefit Heritability Heterozygote High temperature of physical object Human Human body Image Infection Invaded Investigation Kidney Life Liver Mammals Maps Mediating Meiosis Microscopy Modeling Molecular Morphology Mus Mycoses Necrosis Organ Partner in relationship Pathogenesis Pathogenicity Penetration Phenotype Physiological Population Protocols documentation Role Saccharomyces cerevisiae Saccharomycetales Sampling Shapes Societies Source Spleen Surface Testing Tissues Variant Work Yeast Model System Yeasts candidate identification causal variant clinically relevant design experimental study follow-up fungal genetics fungus gene cloning genetic variant human pathogen insight microbial model organism opportunistic pathogen pathogenic fungus pleiotropism transcriptome sequencing

Adhesions Affect Alleles Antifungal Therapy Bar Codes Blood - brain barrier anatomy Body Temperature Brain CRISPR/Cas technology Candida albicans Candidate Disease Gene Cells Chromosome Mapping Clinical Cloning Cre-LoxP Data Development Diploidy Dissection Gene Expression Genes Genetic Genotype Haploidy Health Benefit Heritability Heterozygote High temperature of physical object Human Human body Image Infection Invaded Investigation Kidney Life Liver Mammals Maps Mediating Meiosis Microscopy Modeling Molecular Morphology Mus Mycoses Necrosis Organ Partner in relationship Pathogenesis Pathogenicity Penetration Phenotype Physiological Population Protocols documentation Role Saccharomyces cerevisiae Saccharomycetales Sampling Shapes Societies Source Spleen Surface Testing Tissues Variant Work Yeast Model System Yeasts candidate identification causal variant clinically relevant design experimental study follow-up fungal genetics fungus gene cloning genetic variant human pathogen insight microbial model organism opportunistic pathogen pathogenic fungus pleiotropism transcriptome sequencing

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项目摘要

Project Summary Opportunistic fungal infections can be life-threatening and difficult to treat. Identifying the genetic and molecular mechanisms that enable fungi to persist in humans could have major health benefits for society, potentially even enabling the development of more effective antifungal therapies. The model organism Saccharomyces cerevisiae is itself an opportunistic human pathogen, with many strains isolated from clinical infections. The ability to infect and persist within humans is not universal among S. cerevisiae strains. Clinical S. cerevisiae isolates tend to be highly heterozygous diploids that can grow at higher temperatures and invade into surfaces. However, rigorous genetic dissection of S. cerevisiae’s persistence and pathogenicity within mammalian hosts is needed. To begin such work, we used chromosomally- encoded barcodes and lineage tracking to phenotype a panel of genotyped haploid progeny from a budding yeast cross in mice. The specific cross employed was between a haploid derivative of a clinical isolate and the reference strain. Linkage mapping identified dozens of loci influencing fungal persistence within a mammalian host, many of which lack previously identified candidate genes and show host organ-dependent effects. Following our work, major questions remain unanswered, including the genetic, molecular, and physiological mechanisms underlying yeast persistence and yeast-host interactions; how alleles at causal loci shape the phenotypes of highly heterozygous diploids resembling clinical isolates; the role of surface attachment and invasion in persistence and pathogenicity; and whether the effects of causal loci contributing to fungal pathogenicity have effects that depend on host genotype. Here, we will extend our work by (1) studying mechanisms causing yeast persistence in particular organs by cloning causal genes in yeast, as well as by using cutting-edge microscopy and RNA-seq to analyze yeast-host interactions; (2) testing how combinations of pathogenicity alleles combine in highly heterozygous diploid yeast strains; (3) analyzing how the ability to attach to and invade into surfaces influences the pathogenicity of cross progeny; and (4) examining the genetics of fungal pathogenicity across genetically distinct mouse hosts. Our proposal will utilize the untapped potential of the budding yeast model system to provide concrete insights into the genetics and molecular mechanisms underlying opportunistic fungal pathogenicity.

项目摘要机会性真菌感染可能是威胁生命的，难以治疗。识别使真菌能够在人类中持续的遗传和分子机制可能具有重大对社会的健康益处，甚至有可能发展更有效的发展抗真菌疗法。酿酒酵母的模型生物体葡萄糖本身就是机会主义人类病原体，从临床感染中分离出许多菌株。感染和在酿酒酵母菌株中，人类持续存在并不是普遍的。酿酒酵母临床分离株往往是高度杂合的二倍体，可以在较高的温度下生长入侵表面。但是，酿酒酵母的持久性和需要哺乳动物宿主内的致病性。为了开始这样的工作，我们在染色体上使用了编码的条形码和谱系跟踪到表型，一个基因分型单倍体进度的面板来自小鼠的萌芽酵母十字。特定的十字在单倍体之间临床分离株和参考应变的衍生物。链接映射确定了数十个基因座影响哺乳动物宿主内的真菌持久性，其中许多以前缺乏候选基因并显示宿主器官依赖性作用。遵循我们的工作，主要问题保持未解决，包括遗传，分子和物理机制酵母持久性和酵母 - 主持人相互作用；因果基因座的等位基因如何塑造表型类似于临床分离株的高度杂合二倍体；表面附着和持久性和致病性的入侵；以及因果基因座的影响是否有助于真菌致病性的作用取决于宿主基因型。在这里，我们将扩大我们的工作通过（1）研究机制，特别是通过克隆催化的机构来引起酵母的持久性酵母中的基因以及使用尖端显微镜和RNA-Seq分析酵母宿主互动；（2）测试致病等位基因的组合如何在高度中结合杂合二倍体酵母菌菌株；（3）分析如何附着并入侵的能力表面会影响交叉进展的致病性；（4）检查真菌的遗传学跨基因小鼠宿主的致病性。我们的建议将利用未开发的萌芽的酵母模型系统的潜力，可以为遗传学和机会性真菌致病性的分子机制。