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Within-patient Candida auris strain diversity in a tertiary hospital

三级医院患者内耳念珠菌菌株多样性

基本信息

批准号：
10732309
负责人：
M. Hong Thi NGUYEN
金额：
$ 23.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10732309
关键词：
Adherence Aneuploidy Antibiotic Resistance Antifungal Agents Blood Blood Circulation Candida Candida albicans Candida auris Cell Wall Cells Clinical Microbiology Copy Number Polymorphism Data Diploidy Disease Outbreaks Environment Exhibits Foundations Fungal Drug Resistance Gene Dosage Genes Genetic Genetic Determinism Genetic Variation Genome Genomics Genotype Growth Haploidy Hematogenous Hospitals In Vitro Individual Infection International Karyotype Lipase Microbial Biofilms Microbial Genetics Minimum Inhibitory Concentration measurement Morphogenesis Morphology Multi-Drug Resistance Mutation Mycoses Organism Paper Pathogenesis Pathogenicity Patient Care Patients Peptide Hydrolases Pharmaceutical Preparations Phenotype Phylogeny Point Mutation Polyploidy Population Predisposition Process Production Public Health Regulation Research Design Resistance Resistance development Sepsis Single Nucleotide Polymorphism Site Sterility Testing Treatment Failure Variant Virulence Yeasts antibiotic tolerance biological adaptation to stress carbapenem resistance chronic infection clinically relevant clinically significant echinocandin resistance falls fitness genetic variant genome sequencing health organization individual patient insight mortality mouse model mutant neutrophil novel population based priority pathogen recurrent infection resistant Klebsiella pneumoniae response stem treatment response whole genome

项目摘要

Project Summary Candida auris has recently emerged as a cause of invasive infections worldwide that are associated with high mortality rates despite treatment with echinocandins, the frontline class of antifungal agents, and other drugs. C. auris poses unique challenges due to its propensity for antifungal resistance, and ability to persist in hospital environments and cause long-tern outbreaks. C. auris are haploid yeasts that are evolutionarily divergent from diploid Candida like C. albicans and most pathogenic spp. Strains fall in 5 phylogeographic clades. Most infections are caused by clade I, III or IV strains. There is mounting evidence for genetic diversity within clades, including core genome single nucleotide polymorphisms, karyotype alterations, gene copy number variations, polyploidy and aneuploidy. Strains within a given clade also demonstrate differences in antifungal susceptibility, virulence attributes and pathogenicity. To date, few specific genes have been validated as virulence determinants, and pathogenesis and echinocandin tolerance remain poorly understood. Mechanisms of tolerance, resistance, virulence and pathogenesis cannot necessarily be extrapolated from other Candia spp., or between C. auris clades. The long-standing paradigm is that almost all Candida infections of blood or other normally sterile sites stem from a single, clonal organism. However, in preliminary studies, we have shown that at least some C. auris and C. glabrata strains recovered from positive blood cultures from individual patients at our center exhibit unrecognized genotypic and phenotypic diversity. Our data suggest a new, population-based paradigm for Candida infections. The objectives of this project are to characterize the genetic and phenotypic diversity of C. auris strains recovered from individual patients, and to implicate specific C. auris genes and gene variants in echinocandin tolerance and resistance, and in virulence. In aim 1, we will perform short- and long- read whole genome sequencing and establish phylogeny of multiple clade I and III C. auris recovered from cultures from each patient, including at baseline and during persistent and recurrent infections despite echinocandin treatment. We will then test phenotypes of genetically distinct strains from each patient, including echinocandin tolerance and resistance, and virulence-associated phenotypes. In aim 2, we will prioritize genes and gene variants, and create isogenic mutant C. auris strains in clade I and III backgrounds. Isogenic strains will be assessed for echinocandin responses and virulence in vitro and in a mouse model of bloodstream infection. Results will afford new insights into echinocandin responses and pathogenesis by C. auris, and identify genes that contribute to these processes. Our results will provide a foundation for mechanistic studies of echinocandin tolerance, resistance and virulence, and for trials establishing the clinical significance of C. auris genotypic and phenotypic diversity. Our paradigm of microbial genetic diversity has potentially profound implications for patient care, clinical microbiology practice, and understanding of antifungal treatment responses and pathogenesis.

项目总结