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Transcriptional networks governing A. fumigatus virulence

控制烟曲霉毒力的转录网络

基本信息

批准号：
10365846
负责人：
Scott G Filler
金额：
$ 67.11万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365846
关键词：
Abbreviations Antifungal Therapy Aspergillosis Aspergillus Aspergillus fumigatus Attenuated Azole resistance Binding Biology Bone Marrow Candida albicans Cell Communication Cells ChIP-seq Data Defect Development Diagnosis Diagnostic Disease EMSA Electrophoretic Mobility Shift Assay Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Cells Family Foundations Fright Gene Targeting Genes Genetic Transcription Genome Goals Growth Hemagglutinin Histoplasma capsulatum Hypoxia Immunocompromised Host In Vitro Incidence Infection Invaded Investigation Life Lung Mediating Organism Pathogenesis Pathogenicity Pathway interactions Population Predisposition Prevention Proteins Reactive Oxygen Species Regulon Response Elements Role Testing Therapeutic Vaccines Virulence Work chromatin immunoprecipitation experimental study fungus gene product genome-wide high risk improved innovation interest macrophage member mortality mouse model mutant novel novel diagnostics novel therapeutics overexpression promoter targeted treatment trait transcription factor transcriptome sequencing

项目摘要

Abstract Invasive infections due to Aspergillus fumigatus are increasing and are still associated with unacceptably high mortality, even with new therapies. Our understanding of A. fumigatus infection biology is limited. Among 10,180 predicted genes in the A. fumigatus genome, over 95% are uncharacterized, and fewer than 100 genes have demonstrated roles in virulence. It is critical to identify genes that govern virulence and the pathways in which they act because they can point to high priority targets for therapeutic and diagnostic development. We have identified a transcriptional regulator in A. fumigatus, WrpA, that shares limited homology with Candida albicans Wor1 and Histoplasma capsulatum Ryp1. Our preliminary data indicate that WrpA governs the capacity of A. fumigatus to withstand macrophage killing, grow under hypoxic conditions, and invade and damage pulmonary cells in vitro. ΔwrpA deletion mutants have highly attenuated virulence in the mouse model of invasive aspergillosis. Using RNA-seq, we found that WrpA governs the expression of ~15% of genes in the A. fumigatus genome, including multiple transcription factor genes. Our premise is that the WrpA is a master regulator that governs host cell interactions and virulence. In support of this premise, our initial investigations of the WrpA regulon have already revealed novel pathogenicity-related functions of three WrpA-dependent transcription factors, SrbB, Fcr1, and Ndt80. Our goal is to characterize the WrpA regulon in A. fumigatus and to identify downstream effector genes whose products mediate pathogenicity by: 1) identifying the transcription factors that are directly regulated by WrpA and determining their roles in pathogenicity; 2) analyzing selected WrpA- dependent transcription factors and identifying their downstream target genes; and 3) determining the function of effector genes controlled by the WrpA regulon and investigating their roles in virulence. The results of the experiments described in this proposal will enable us to characterize a key transcriptional regulator that governs A. fumigatus pathogenicity and then use this information to identify downstream effector genes, the products of which mediate host cell interactions and virulence. The results of this work will not only provide foundational understanding of A. fumigatus virulence mechanisms, but also hold promise to identify new diagnostic, therapeutic, and vaccine targets.

摘要