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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

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.

项目总结