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In Host Evolution of Nontuberculous Mycobacteria in Cystic Fibrosis

囊性纤维化中非结核分枝杆菌的宿主进化

基本信息

批准号：
9896274
负责人：
PAUL J PLANET
金额：
$ 27.26万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896274
关键词：
16S ribosomal RNA sequencing Aminoglycoside resistance Antibiotic Resistance Antibiotics Attention Bioinformatics Biological Markers Cessation of life Chronic Clinical Microbiology Clinical Research Communicable Diseases Communities Complement Complex Coupled Cystic Fibrosis DNA DNA Sequence Alteration Data Detection Diagnosis Disease Disease Progression Ecology Ecosystem Evolution Future Generations Genes Genetic Recombination Genomic approach Genomics Genotype Goals Grain Human Immune Evasion Immune system Infection Inflammation Intervention Investigation Lead Life Style Lung Lung diseases Macrolides Metabolic Metagenomics Methods Microbial Biofilms Microbiology Modality Molecular Mosaicism Mutation Mycobacterium Infections Natural Selections Noise Nucleotides Organism Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Phylogenetic Analysis Population Population Dynamics Population Heterogeneity Prevalence Property Pulmonary Fibrosis Regimen Research Resistance Respiratory physiology Sampling Severity of illness Specialist Specificity Techniques Testing Time Uncertainty Variant Virulence biobank bioinformatics pipeline bioinformatics tool chronic infection clinical decision-making clinical phenotype clinically relevant cystic fibrosis infection cystic fibrosis patients design extracellular fitness gene interaction genome sequencing insertion/deletion mutation insight large datasets lung microbiota member microbial microbial community microbiome microbiota microorganism interaction non-tuberculosis mycobacteria novel outcome forecast pathogen predictive marker prospective rRNA Genes reconstruction respiratory microbiota tool treatment duration whole genome

项目摘要

PROJECT SUMMARY Nontuberculous mycobacteria (NTM) have emerged as an increasingly common cause of severe lung disease in patients with cystic fibrosis (CF). Unfortunately, diagnosis, prognosis, and treatment remain exceedingly difficult. Infection can result in more rapid decline in lung function and even death. During chronic infection, NTM frequently become resistant to the most effective antibiotic regimens, and infection is typically difficult or impossible to eradicate. Moreover, little is known about the molecular determinants of pathogenesis, inflammation, immune evasion, and persistence in NTM-driven disease. Here we propose an approach that follows the genomic evolution of NTM over time in chronically infected CF patients. We will rigorously apply whole genome sequencing and a battery of phylogenomic analyses to identify genetic changes in NTM strains that are likely to increase pathogen fitness. Because the CF lung harbors a complex and dynamic microbial ecosystem we will also comprehensively assess co-inhabiting microbiota, including well-known CF pathogens and other members of the respiratory microbiota. While some microbiota may compete with NTM, others may act to reinforce NTM infections, and some could even serve as reservoirs for genes that are beneficial to the pathogen (e.g., antibiotic resistance). We hypothesize that NTM undergoes predictable phenotypic and genotypic changes, which are likely influenced by co-infecting microbiota, to allow for enhanced NTM fitness, virulence, and persistence in the lung. AIM 1 examines longitudinal isolates from CF patients infected with NTM, emphasizing a deep sampling approach and population-level estimates of microbial diversity, mutation, recombination, and natural selection. Evolutionary changes in NTM populations will be associated with detailed clinical and phenotypic information, to identify genes that may be involved in antibiotic resistance, virulence, and persistence. AIM 2 uses a novel, whole 16S-rRNA gene sequencing approach to examine the cross-sectional and longitudinal interaction of NTM with other lung microbiota including co- infecting CF pathogens. We will compare patients with and without NTM and associate differences in the microbial population. Completing these aims will identify genes and microbial interactions that can be targeted for future functional studies aimed at uncovering the basic mechanisms and strategies that allow NTM adaptation during in-host evolution. We will also test and validate bioinformatic pipelines and sampling strategies that can be used in future NTM phylogenomic studies, and we will gain a fine-grained understanding of the NTM population dynamics during chronic infection. Characterizing in-host NTM adaptation will allow us to more effectively identify strains that may be difficult to eradicate or treat, and design new, targeted interventions to subvert these adaptations.!

项目总结