Parallel phenotyping to dissect genetic determinants of bacterial strain diversity

平行表型剖析细菌菌株多样性的遗传决定因素

基本信息

批准号：
10509033
负责人：
Allison Carey
金额：
$ 43.37万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-09 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10509033
关键词：
Acute Address Antibiotic Therapy Antibiotics Bacteria Bacterial Genes Bacterial Genome Bacterial Infections Bar Codes Biodiversity Bioinformatics Biological Catalogs Characteristics Chronic Clinical Communicable Diseases Data Development Diagnostic Disease Drug Exposure Environment Experimental Genetics Foundations Genes Genetic Genetic Determinism Genetic Variation Genomic approach Genomics Genotype Heterogeneity Human Impairment In Vitro Incidence Infection Link Maps Measurement Methods Microbe Molecular Morbidity - disease rate Mus Mutation Mycobacterium avium Mycobacterium tuberculosis Opportunistic Infections Organism Pathogenesis Pathogenicity Pathway interactions Phenotype Postdoctoral Fellow Predisposition Research Techniques Technology Testing Therapeutic Treatment outcome Vaccination Vaccines Virulence Work antibiotic tolerance antimicrobial bacterial fitness chronic infection clinically relevant comparative genomics design disease phenotype drug efficacy emerging antimicrobial resistance emerging pathogen experimental study fitness genome wide association study improved in vivo innovation insight interest microbial mouse model mycobacterial novel novel strategies pathogen phenotypic data programs public health intervention response skills therapeutically effective tool trait treatment response vaccine efficacy

项目摘要

PROJECT SUMMARY All pathogens possess genetic diversity that can impact clinically relevant phenotypes such as virulence, susceptibility to drugs, and vaccine efficacy. In the post-genomic era, our ability to catalog microbial genotypes has far outstripped our capacity to profile microbial phenotypes. This limits our ability to build genotype- phenotype maps for traits of interest and hinders the development of broadly effective new antimicrobials, vaccines, and public health interventions. To address this challenge, I developed a molecular barcoding approach that permits parallel fitness phenotyping of hundreds of bacterial clinical isolates in a single in vitro or in vivo experiment. I developed and validated this novel approach in the pathogen Mycobacterium tuberculosis and uncovered strain-specific differences in bacterial fitness during infection and following vaccination in the mouse model. Here, I propose to use this novel tool to interrogate the genetic basis of phenotypic heterogeneity in a related mycobacterial pathogen, Mycobacterium avium (MAC). MAC is an environmental microbe that can cause chronic and treatment-recalcitrant infections and is increasing in incidence. A major challenge in the management of MAC disease is the variability in disease course and treatment outcome, and the bacterial determinants of this variability are unknown. Here, I will leverage my strain barcoding approach and the natural biodiversity of this microbe to elucidate genetic determinants and molecular mechanisms of MAC pathogenicity and antibiotic response. These efforts will inform the development of improved diagnostics and therapeutics for this, and other, chronic bacterial infections. More broadly, this work will provide an intellectual framework and experimental toolkit to uncover the biological basis of heterogeneity in infectious disease phenotypes.

项目摘要所有病原体都有遗传多样性，可以影响临床相关的表型，例如毒力，对药物的敏感性和疫苗功效。在基因组后时代，我们有能力分类微生物基因型我们概述微生物表型的能力远远超过了。这限制了我们建立基因型的能力 - 具有兴趣特征的表型图，并阻碍了广泛有效的新抗微生物的发展，疫苗和公共卫生干预措施。为了应对这一挑战，我开发了一个分子条形码允许在单个体外或体内实验。我在病原体分枝杆菌结核病中开发并验证了这种新颖的方法以及在感染期间和疫苗接种后未发现细菌适应性的菌株特异性差异鼠标模型。在这里，我建议使用这种新颖的工具来询问表型的遗传基础相关分枝杆菌病原体，分枝杆菌（MAC）中的异质性。 Mac是环境可能引起慢性和治疗核心感染并发病率增加的微生物。专业 MAC疾病管理中的挑战是疾病病程和治疗结果的可变性，以及该变异性的细菌决定因素尚不清楚。在这里，我将利用我的应变条形码方法以及该微生物的自然生物多样性，以阐明遗传决定因素和分子机制 MAC致病性和抗生素反应。这些努力将为改进诊断的发展提供信息和其他慢性细菌感染的治疗剂。更广泛地，这项工作将提供智力框架和实验工具包，以发现传染性的异质性生物学基础疾病表型。