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Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal Pathogen

主要人类真菌病原体的形态发生、共生性和毒力的系统分析

基本信息

批准号：
10709905
负责人：
LEAH Elizabeth Cowen
金额：
$ 61.5万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709905
关键词：
Address Affect Alleles Aneuploidy Animal Disease Models Anoxia Antifungal Agents Bar Codes Biological Biological Assay Blood Circulation Candida albicans Candidiasis Carbon Carbon Dioxide Cell physiology Cells Cellular Morphology Cellular Structures Cessation of life Clinical Collection Communities Cost of Illness Cues Data Set Defect Development Diagnostic tests Diploidy Disease Dissection Drug Targeting Drug resistance Economics Engineering Essential Genes Filament Filtration Fostering Funding Fungi Model Gene Expression Genes Genetic Genome Health Hospitals Human Image Analysis Immune In Vitro Infection Investments Life Macrophage Messenger RNA Methods Modeling Molecular Morphogenesis Mus Mutation Organism Pathogenesis Pathogenicity Patients Persons Phagocytosis Pharmaceutical Preparations Phenotype Positioning Attribute Protocols documentation RNA RNA Splicing Resolution Resources Saccharomycetales Sepsis Serum Source Symbiosis Systemic infection Systems Biology Temperature Testing Tetracyclines Toxic effect Transcript Validation Virulence Work Yeast Model System Yeasts drug testing fitness functional genomics fungus gene replacement genetic analysis genetic approach genetic resource genome resource genome wide screen genome-wide genomic platform gut colonization high resolution imaging high throughput analysis human disease human pathogen immunoregulation in vitro testing in vivo insight machine learning model mortality mouse model mutant next generation sequencing novel novel therapeutic intervention opportunistic pathogen pathogen pathogenic fungus programs promoter public database response screening social trait transcription factor transcriptomics whole genome

项目摘要

SUMMARY/ABSTRACT Fungal pathogens pose a devastating threat to human health, infecting billions of people worldwide and causing more than 1.5 million deaths each year. Candida albicans is one of the most pervasive fungal pathogens, killing almost 40% of people suffering from bloodstream infections. Treating these infections is extremely difficult, as fungi are closely related to humans and there are very few drugs that kill the fungus without host toxicity. With the emergence of drug resistance, the development of new therapeutic strategies is now crucial. To address this important clinical need and identify new antifungal drug targets, it is critical to uncover mechanisms that enable C. albicans to cause life-threatening human disease. We are one of the first academic labs to obtain a powerful functional genomics resource that we are uniquely positioned to expand to allow us to test the function of almost every gene in the C. albicans genome. This resource includes a collection of conditional expression strains that covers ~40% of the genome where one allele of a target gene is deleted in the diploid pathogen, and expression of the remaining wild-type allele is governed by the tetracycline-repressible promoter. During the prior funding period we: developed a pipeline to expand the resource to genome scale, optimized a functional genomics platform for massively parallel analysis of fungal virulence traits using next generation sequencing with pooled assays to quantify the relative proportion of each strain, which are uniquely marked with molecular barcodes; optimized high-resolution image analysis of cellular morphology and structures; and developed assays for identifying genes important for commensalism, virulence, and interaction with host immune cells. Our efficient high-throughput analyses established the power of systematic genetic analysis to uncover new biological insights that could not have been predicted based on current paradigms and enabled focused, hypothesis-driven dissection of key mechanisms governing host- pathogen interactions. Our studies will provide the first global analysis of C. albicans morphogenesis, commensalism, and virulence, and will reveal fundamental biological mechanisms that could not be predicted without a systematic genetic approach. Our studies will: 1) complete the collection of tetracycline-repressible conditional expression strains to cover non-essential genes, since genes required for pathogen viability in vitro provide little insight into host adaptation or virulence; 2) identify novel regulators of key virulence traits such as morphogenesis; and 3) identify determinants of C. albicans host adaptation and virulence on a genome scale. Our comprehensive strain resources and compendium of phenotypic profiles will be made available to the community, advancing the field with a publicly accessible database and interpretive machine learning model to maximize insight. This work will provide the most comprehensive functional genomics resource for any fungal pathogen and will reveal genes governing host adaptation, revealing new strategies to cripple fungal pathogens.

摘要/文摘

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insights into the host-pathogen interaction: C. albicans manipulation of macrophage pyroptosis.

深入了解宿主-病原体相互作用：白色念珠菌操纵巨噬细胞焦亡。

DOI：
10.15698/mic2018.12.662
发表时间：
2018
期刊：
Microbial cell (Graz, Austria)
影响因子：
0
作者：
O'Meara,TeresaR;Cowen,LeahE
通讯作者：
Cowen,LeahE

Construction of Candida albicans Strains with ATP-Analog-Sensitive Protein Kinase A and Hog1.

DOI：
10.1128/msphere.00095-23
发表时间：
2023-06-22
期刊：
mSphere
影响因子：
4.8
作者：
通讯作者：

Ent2 Governs Morphogenesis and Virulence in Part through Regulation of the Cdc42 Signaling Cascade in the Fungal Pathogen Candida albicans.

DOI：
10.1128/mbio.03434-22
发表时间：
2023-04-25
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets.

DOI：
10.1038/s41467-021-26850-3
发表时间：
2021-11-11
期刊：
Nature communications
影响因子：
16.6
作者：
Fu C;Zhang X;Veri AO;Iyer KR;Lash E;Xue A;Yan H;Revie NM;Wong C;Lin ZY;Polvi EJ;Liston SD;VanderSluis B;Hou J;Yashiroda Y;Gingras AC;Boone C;O'Meara TR;O'Meara MJ;Noble S;Robbins N;Myers CL;Cowen LE
通讯作者：
Cowen LE

Functional connections between cell cycle and proteostasis in the regulation of Candida albicans morphogenesis.