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Drifting to victory: resolving the paradox of M. tuberculosis evolution

走向胜利：解决结核分枝杆菌进化的悖论

基本信息

批准号：
10407445
负责人：
Caitlin S Pepperell
金额：
$ 45.99万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407445
关键词：
Affect Antibiotics Architecture Autopsy Bacteria Binding Sites Cause of Death Cell Size Cells Clinical Collection Communicable Diseases Communities Complex Data Development Disease Dose Drug resistance Environment Epigenetic Process Evolution Exhibits Exposure to Gene Dosage Gene Expression Regulation Genetic Genetic Transcription Genetic Variation Genomics Goals Growth Human Hypoxia In Vitro Individual Infection Lesion Mediating Microbial Biofilms Molecular Mutation Mycobacterium tuberculosis Outcome Pathogenesis Pathologic Patients Persons Phenotype Population Population Analysis Regimen Research Resources Roentgen Rays Role Serial Passage Shapes Source System Testing Treatment Failure Tuberculosis Variant Work airway epithelium antibiotic tolerance assault experience experimental analysis experimental study genetic variant genomic data genomic locus insight neutrophil novel pathogen pathogenic bacteria resistant strain response stressor tool transcription factor tuberculosis treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide. Although TB is treatable, treatments are prolonged, complex, and difficult for many people to tolerate. Mycobacterium tuberculosis (M. tb) also readily acquires drug resistance and global efforts to control TB are threatened by the increasing problem of drug resistance. M. tb is capable of assembling into biofilm communities capable of withstanding lethal doses of antibiotics and this phenomenon likely contributes to difficulties in treating and controlling TB. We have developed an in vitro system to study adaptation M. tb within biofilms. Leveraging analyses of these experimental populations with those of a well characterized natural population of M. tb, we discovered that M. tb strains separated by a small number of genetic differences exhibit a surprising array of phenotypic differences. Our preliminary data point to regulatory mechanisms underlying these changes. Contextualizing these data with our recent discoveries in M.tb evolutionary population genomics at regional and global scales, we hypothesize that M. tb adaptation occurs at the scale of individual hosts while large scale phenomena act primarily as a constraint on adaptation. Our major objective now is to delineate the mechanisms underlying observed phenotypic differences in these natural and experimental populations.

项目总结/文摘