Inhibition of Candida virulence and biofilm formation by a bacterial peptide
细菌肽抑制念珠菌毒力和生物膜形成
基本信息
- 批准号:10621569
- 负责人:
- 金额:$ 7.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActinsAdherenceAdhesionsAffectAmino AcidsAnimal ModelAntibioticsAntifungal AgentsAreaAttenuatedBacteriaBacterial AdhesinsBindingBiochemicalBiogenesisBiologicalBiologyCaenorhabditis elegansCandidaCandida albicansCandidiasisCell Surface ProteinsCell WallCell surfaceCellsChemicalsDataDevelopmentDisease modelEnterococcus faecalisEpithelialEpithelial CellsFelis catusGenerationsGenesGeneticGlycoproteinsGoalsGrowthHIV SeropositivityHead and neck structureHomologous GeneHuman MicrobiomeImmunocompromised HostIn VitroInfantInfectionInflammationInvestigationKnowledgeLabelMalignant NeoplasmsMedicalMembrane MicrodomainsMicrobial BiofilmsModelingMorbidity - disease rateMorphogenesisMusOralOral candidiasisOral cavityOutcomePathway interactionsPatientsPeptide HydrolasesPeptidesPost-Translational Protein ProcessingProcessProteinsPublic HealthRadiationResearchRiskRoleSignal PathwaySiteSourceSteroidsSurfaceTestingTherapeuticVertebratesVirulenceWorkYeastsbasecell envelopecell growthchemotherapydesigndisulfide bondefficacy testingexperimental studyfungusgastrointestinalgene productgenetic approachgut colonizationimmunosuppressedinnovationmacrophagemicroorganism interactionmouse modelmutantnanomolarnormal microbiotanovelnovel strategiesnovel therapeuticsoral cavity epitheliumoral infectionoropharyngeal thrushpreventtherapeutic developmenttissue/cell culturetreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
The medical condition oropharyngeal candidiasis (OPC) is a major source of oral morbidity in patient groups
including the immunosuppressed (cancer and AIDS patients) and those taking broad-spectrum antibiotics. We
recently identified a peptide produced by Enterococcus faecalis that inhibits the hyphal morphogenesis and
biofilm formation of the primary causative agent of OPC, Candida albicans. The research proposed in this ap-
plication seeks to understand how the mature form of this peptide, EntV, is generated, how it targets C. albi-
cans hyphal morphogenesis, and the extent to which it protects against OPC, thereby filling a critical gap in our
knowledge and providing new avenues for the development of therapeutics. The long-term goal of this re-
search is to develop novel strategies for treating and preventing oropharyngeal candidiasis. The objective of
this application is to determine the generation, mode of action and therapeutic potential of EntV. The central
hypothesis is that secreted and processed EntV acts on signaling pathway(s) that controls hyphal development
in C. albicans resulting in protection from candidiasis. The rationale for this research is that identification of the
mechanism by which EntV inhibits the formation of the invasive form of C. albicans will lead to new treatment
strategies. By pursing three aims, the objective of this application will be attained. Aim #1 will elucidate how the
active form of EntV is generated. Using both genetic and biochemical approaches, we will test the hypothesis
that the proteases GelE and/or SprE are required for cleavage, and disulfide bond formation is catalyzed by a
DsbA homolog. In Aim #2, the genes/pathways of C. albicans that are targeted by E. faecalis to inhibit hyphal
morphogenesis will be determined using cell biological and genetic approaches. Based on preliminary data,
the working hypothesis is that EntV interacts directly with one of several known discrete subdomains on the C.
albicans cell surface to disrupt cell-cell and cell-substrate adherence, both of which are essential for biofilm
formation. The efficacy of EntV and related peptides in protecting against C. albicans infection will be tested in
Aim #3. Tissue culture cells (macrophages and oral epithelial cells) and mouse models of OPC and gastroin-
testinal colonization will be utilized. We postulate that EntV will protect against C. albicans infection and can-
didiasis in the nanomolar range. The significance of this contribution will be the knowledge of how a bacterial
peptide inhibits C. albicans hyphal morphogenesis, potentially opening new avenues for therapeutic design.
Targeting hyphal morphogenesis as an area for the possible development of novel therapeutics is innovative,
as current antifungals are directed against the integrity or growth of the cell envelope. Additional benefits of this
research include new knowledge in the fields of bacterial peptide generation, fungal morphotype switching, and
inter-kingdom microbial interactions.
项目总结/文摘
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Host-derived reactive oxygen species trigger activation of the Candida albicans transcription regulator Rtg1/3.
- DOI:10.1371/journal.ppat.1011692
- 发表时间:2023-09
- 期刊:
- 影响因子:6.7
- 作者:
- 通讯作者:
The pathogenesis of cardiac microlesion formation during severe bacteremic infection.
- DOI:10.1371/journal.ppat.1009021
- 发表时间:2020-11
- 期刊:
- 影响因子:6.7
- 作者:Brown AO;Garsin DA
- 通讯作者:Garsin DA
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Danielle A Garsin其他文献
Vertebrate and invertebrate animal infection models of emCandida auris/em pathogenicity
Candida auris(耳念珠菌)致病性的脊椎动物和无脊椎动物感染模型
- DOI:
10.1016/j.mib.2024.102506 - 发表时间:
2024-08-01 - 期刊:
- 影响因子:7.500
- 作者:
Melissa Martinez;Danielle A Garsin;Michael C Lorenz - 通讯作者:
Michael C Lorenz
Danielle A Garsin的其他文献
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{{ truncateString('Danielle A Garsin', 18)}}的其他基金
Inhibition of Candida Virulence and Biofilm Formation by a Bacterial Peptide
细菌肽抑制念珠菌毒力和生物膜形成
- 批准号:
10302700 - 财政年份:2021
- 资助金额:
$ 7.6万 - 项目类别:
Ethanolamine utilizing bacterial microcompartments in host cells
乙醇胺利用宿主细胞中的细菌微区室
- 批准号:
10495242 - 财政年份:2021
- 资助金额:
$ 7.6万 - 项目类别:
Ethanolamine utilizing bacterial microcompartments in host cells
乙醇胺利用宿主细胞中的细菌微区室
- 批准号:
10385013 - 财政年份:2021
- 资助金额:
$ 7.6万 - 项目类别:
Inhibition of Candida virulence and biofilm formation by a bacterial peptide
细菌肽抑制念珠菌毒力和生物膜形成
- 批准号:
10407531 - 财政年份:2018
- 资助金额:
$ 7.6万 - 项目类别:
Post-initiation regulatory mechanisms controlling ethanolamine utilization
控制乙醇胺利用的引发后调节机制
- 批准号:
9193056 - 财政年份:2015
- 资助金额:
$ 7.6万 - 项目类别:
Mechanism of Gene Regulation by RNA-Binding ANTAR Proteins
RNA结合ANTAR蛋白的基因调控机制
- 批准号:
8325259 - 财政年份:2011
- 资助金额:
$ 7.6万 - 项目类别:
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