Genomic diversity of Candida bloodstream infections
念珠菌血流感染的基因组多样性
基本信息
- 批准号:10358615
- 负责人:
- 金额:$ 21.9万
- 依托单位:
- 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:2021-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAntifungal AgentsAntimicrobial susceptibilityAttentionBacteriaBiological ProcessBloodBlood CirculationCandidaCandida albicansCandida glabrataCandidiasisCell WallCellsClinicalClinical MicrobiologyComplementDNA Sequence RearrangementDataDiploidyDiseaseExhibitsExperimental ModelsFoundationsFungal Drug ResistanceGastrointestinal tract structureGenesGeneticGenetic DeterminismGenetic VariationGenetic studyGenomeGenomicsGrowthHaploidyHematogenousHumanIn VitroInfectionLaboratoriesMorphologyMucous MembraneOrganismOrganism CloningPathogenesisPatientsPhenotypePhylogenetic AnalysisPopulationPopulation HeterogeneityRecurrenceRecurrent diseaseRegulationResistanceResistance developmentSepsisSingle Nucleotide PolymorphismSiteState HospitalsStimulusSurfaceTestingTimeTreatment FailureUnited StatesVirulenceVirulentcandidemiachronic infectionclinically relevantechinocandin resistancegenetic variantgenome analysisgenome sequencingindividual patientinsertion/deletion mutationinsightmortalitymouse modelmutantnanoporenovelopportunistic pathogenpathogenrecurrent infectionreference genomeresponsestemtreatment responsewhole genome
项目摘要
Project Abstract
Candida species are fourth leading cause of bloodstream infections (BSIs) in United States hospitals. BSIs due
to C. albicans and C. glabrata, the most common Candida species to cause invasive infections, are 20%-40%
despite treatment with echinocandins, the frontline antifungal agents. Echinocandin resistance is increasingly
described among C. albicans and C. glabrata clinical isolates. Nevertheless, most echinocandin treatment
failures are not associated with emergence of resistance. Echinocandin tolerance, in which Candida growth is
inhibited but cells remain viable, may predispose to subsequent development of resistance, but clinical relevance
of this phenotype is unclear. The longstanding paradigm is that almost all candidemia and other BSIs stem from
a single, clonal organism. In preliminary studies, however, we showed by whole genome sequencing (WGS)
and phylogenetic analyses that C. albicans and C. glabrata BSIs are caused by mixed populations of genetically
diverse strains, which are not typically recognized by the clinical microbiology laboratory. Upon deeper analysis
of C. albicans WGS data, we found that gene variants identified in multiple patients with BSIs were enriched for
biological processes that are known to be important in echinocandin responses and virulence. Our objectives in
this project are to characterize in greater detail the genetic and phenotypic diversity of bloodstream C. albicans
and C. glabrata strains, with particular attention to strains associated with persistent or recurrent infections
despite echinocandin treatment, and to implicate specific Candida genes and gene variants in echinocandin
tolerance, resistance and virulence. We hypothesize that by studying strains from longitudinal BCs and extra-
blood sites of patients with persistent or recurrent C. albicans or C. glabrata bloodstream infections despite
echinocandin treatment, we will identify novel genes or gene variants that are responsible for echinocandin
tolerance/resistance and virulence. In our first aim, we will complete WGS and analyses of C. albicans and C.
glabrata from baseline BCs (10 patients each). Then, we will perform WGS and analyses of strains from positive
longitudinal blood and extra-blood cultures collected during or after echinocandin treatment. Finally, we will
determine phenotypes of genetically diverse strains from BCs, including echinocandin tolerance and resistance.
In our second aim, we will construct isogenic mutant and complemented C. albicans and C. glabrata strains for
genes and gene variants that are identified and prioritized in aim 1. We will test strains for phenotypes in vitro
and for echinocandin treatment responses and virulence using mouse models of hematogenously disseminated
infections. Results will affirm the extent and type of C. albicans and C. glabrata genetic diversity in BCs, afford
new insights into Candida responses to echinocandins during persistent or recurrent BSIs, and identify novel
genetic determinants of echinocandin treatment failure and virulence. Our findings will challenge current clinical
and microbiology laboratory practices, and provide a foundation for studies of genetic diversity during BSIs by
other Candida species and bacteria, and mechanisms of antifungal tolerance, resistance and pathogenesis.
项目摘要
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Unveiling the Microbial Realm with VEBA 2.0: A modular bioinformatics suite for end-to-end genome-resolved prokaryotic, (micro)eukaryotic, and viral multi-omics from either short- or long-read sequencing.
使用 VEBA 2.0 揭开微生物领域的面纱:模块化生物信息学套件,用于通过短读长或长读长测序进行端到端基因组解析的原核生物、(微)真核生物和病毒多组学。
- DOI:10.1101/2024.03.08.583560
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Espinoza,JoshL;Phillips,Allan;Prentice,MelanieB;Tan,GeneS;Kamath,PaulineL;Lloyd,KarenG;Dupont,ChrisL
- 通讯作者:Dupont,ChrisL
Genotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures.
- DOI:10.1038/s41467-023-41509-x
- 发表时间:2023-09-22
- 期刊:
- 影响因子:16.6
- 作者:Badrane, Hassan;Cheng, Shaoji;Dupont, Christopher L.;Hao, Binghua;Driscoll, Eileen;Morder, Kristin;Liu, Guojun;Newbrough, Anthony;Fleres, Giuseppe;Kaul, Drishti;Espinoza, Josh L.;Clancy, Cornelius J.;Nguyen, M. Hong
- 通讯作者:Nguyen, M. Hong
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M. Hong Thi NGUYEN其他文献
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{{ truncateString('M. Hong Thi NGUYEN', 18)}}的其他基金
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
- 批准号:
10732309 - 财政年份:2023
- 资助金额:
$ 21.9万 - 项目类别:
Antibiotic resistance among hypermutator carbapenem resistant Klebsiella pneumoniae
超突变碳青霉烯类耐药肺炎克雷伯菌的抗生素耐药性
- 批准号:
10650872 - 财政年份:2022
- 资助金额:
$ 21.9万 - 项目类别:
Antibiotic resistance among hypermutator carbapenem resistant Klebsiella pneumoniae
超突变碳青霉烯类耐药肺炎克雷伯菌的抗生素耐药性
- 批准号:
10532461 - 财政年份:2022
- 资助金额:
$ 21.9万 - 项目类别:
Genomic diversity of Candida bloodstream infections
念珠菌血流感染的基因组多样性
- 批准号:
10206449 - 财政年份:2021
- 资助金额:
$ 21.9万 - 项目类别:
Invasive aspergillosis complicating severe influenza
侵袭性曲霉病并发严重流感
- 批准号:
10041825 - 财政年份:2020
- 资助金额:
$ 21.9万 - 项目类别:
Invasive aspergillosis complicating severe influenza
侵袭性曲霉病并发严重流感
- 批准号:
10180901 - 财政年份:2020
- 资助金额:
$ 21.9万 - 项目类别:
Candida albicans gene expression during intra-abdominal infections
腹腔内感染期间白色念珠菌基因表达
- 批准号:
8829141 - 财政年份:2014
- 资助金额:
$ 21.9万 - 项目类别:
Candida albicans gene expression during intra-abdominal infections
腹腔内感染期间白色念珠菌基因表达
- 批准号:
8642813 - 财政年份:2014
- 资助金额:
$ 21.9万 - 项目类别:
Mycology Research Unit: In Vivo Induced Fungal Antigens
真菌学研究单位:体内诱导真菌抗原
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7635201 - 财政年份:2004
- 资助金额:
$ 21.9万 - 项目类别:
Mycology Research Unit: In Vivo Induced Fungal Antigens
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- 批准号:
7074600 - 财政年份:2004
- 资助金额:
$ 21.9万 - 项目类别:
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