Candida albicans responses to antifungals and cell wall stress
白色念珠菌对抗真菌药物和细胞壁应激的反应
基本信息
- 批准号:9666582
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAbdominal InfectionAntibioticsAntifungal AgentsAntifungal TherapyAttenuatedBiological ProcessBlood CirculationCandidaCandida albicansCandidiasisCaspofunginCathetersCell WallCell membraneCellsChemotherapy-Oncologic ProcedureChitinCytokinesisDataDiagnostic testsDisseminated candidiasisEnzymesExhibitsExposure toExpression ProfilingFutureGastrointestinal Surgical ProceduresGene ExpressionGene Expression ProfilingGene TargetingGenesHealthHematogenousHospitalsHost DefenseHumanIn VitroIndustrial fungicideInfectionIntra-abdominalIntravenousKidney FailureLinkMediatingMicafunginMissionModelingMorphogenesisMusNeutropeniaOutcomePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhosphatidylinositolsPhosphoric Monoester HydrolasesPlasma CellsPredispositionProteinsRegulationResistanceRisk FactorsRoleSiteStressTestingTissuesTreatment FailureVeteransVirulenceVirulence FactorsYeastsbiological adaptation to stresscandidemiadesignechinocandin resistanceeffective therapygene functionglucan synthasehigh riskhuman pathogenimmunosuppressedimprovedin vivoinsightmortalitymouse modelmutantnovel diagnosticsnovel therapeuticsoverexpressionpathogenpathogenic fungusreconstitutionresponsetranscription factortranscriptome sequencing
项目摘要
Candida albicans causes invasive infections like candidemia and intra-abdominal canididiasis (IAC) that are
common among hospitalized patients. The C. albicans cell wall is central to the pathogenesis of candidiasis, but
mechanisms that link cell wall regulation and virulence are only beginning to be understood. Cell wall-active
echinocandin antifungals are front-line agents against invasive candidiasis. However, mortality rates among
patients with candidemia or IAC who are treated with echinocandins are 40% or higher. We have shown that C.
albicans rapidly delocalizes phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2) and septins as part of the natural
response to echinocandins. Targeted disruption of C. albicans INP51, which encodes a PI(4,5)P2-specific 5'-
phosphatase, results in PI(4,5)P2 and septin dysregulation, echinocandin hypersusceptibility, over-activation of
the PKC-Mkc1 cell wall integrity pathway in response to stress, cell wall damage gene expression profiles in
absence of stress, and attenuated virulence during hematogenously disseminated candidiasis (DC) and IAC in
mice. Our data demonstrate that balanced PI(4,5)P2 regulation promotes protective cell wall responses and
virulence through activation of the PKC-Mkc1 pathway, while PI(4,5)P2 dysregulation is associated with
deleterious septin, plasma membrane and cell wall responses. More recently, we established that C. albicans
CAS5, which encodes a major transcription factor downstream of Inp51 and Mkc1, and RIM101, which encodes
a transcription factor induced at pH>5.5, during IAC and in the inp51 mutant, are important determinants of
echinocandin responses and virulence. The objectives of this project are to determine mechanisms by which C.
albicans CAS5 and RIM101 regulate cell wall stress responses and contribute to echinocandin resistance and
the pathogenesis of invasive candidiasis. In aim 1, we will validate genes regulated by C. albicans CAS5 during
IAC as virulence determinants, and identify their biologic functions. Toward these ends, we will use RNA-Seq
to perform transcriptional profiling of cas5 null mutant and CAS5 reconstitution strains in vitro and temporal-
spatially during IAC of mice. Then, we will validate certain Cas5-regulated genes as virulence determinants by
testing mutant strains in the mouse models of IAC and DC, and characterize their functions. In aim 2, we will
use similar approaches to validate genes regulated by RIM101 during IAC as virulence determinants, and identify
their functions. In aim 3, we will identify genes regulated by C. albicans CAS5 and RIM101 in response to
micafungin during IAC, and validate their roles in echinocandin resistance or susceptibility. We will perform
RNA-Seq transcriptional profiling of C. albicans wild-type SC5314, cas5, rim101 and the respective reconstitution
strains in response to micafungin in vitro and during IAC, and validate certain genes as contributing to micafungin
responses in vivo . This project will provide new insights into echinocandin and cell wall stress responses by C.
albicans that are relevant to the treatment and pathogenesis of invasive candidiasis, and which have the potential
to identify new therapeutic and diagnostic targets.
白色念珠菌引起侵袭性感染,如念珠菌血症和腹内念珠菌病 (IAC),
常见于住院患者。白色念珠菌细胞壁是念珠菌病发病机制的核心,但是
连接细胞壁调节和毒力的机制才刚刚开始被理解。细胞壁活性
棘白菌素抗真菌药是对抗侵袭性念珠菌病的一线药物。然而,死亡率
使用棘白菌素治疗的念珠菌血症或 IAC 患者的比例为 40% 或更高。我们已经证明,C.
白色念珠菌迅速使磷脂酰肌醇-(4,5)-二磷酸 (PI(4,5)P2) 和脓毒蛋白离域,作为天然产物的一部分
对棘白菌素的反应。靶向破坏白色念珠菌 INP51,编码 PI(4,5)P2 特异性 5'-
磷酸酶,导致 PI(4,5)P2 和 septin 失调、棘白菌素过敏、过度激活
PKC-Mkc1 细胞壁完整性通路响应应激、细胞壁损伤基因表达谱
血行播散性念珠菌病 (DC) 和 IAC 期间缺乏应激,毒力减弱
老鼠。我们的数据表明,平衡的 PI(4,5)P2 调节可促进保护性细胞壁反应,
通过激活 PKC-Mkc1 途径产生毒力,而 PI(4,5)P2 失调与
有害的脓毒症、质膜和细胞壁反应。最近,我们确定白色念珠菌
CAS5,编码 Inp51 和 Mkc1 下游的主要转录因子,RIM101,编码
在 IAC 和 inp51 突变体中,pH>5.5 诱导的转录因子是重要的决定因素
棘白菌素反应和毒力。该项目的目标是确定 C.
白色念珠菌 CAS5 和 RIM101 调节细胞壁应激反应并有助于棘白菌素耐药性和
侵袭性念珠菌病的发病机制。在目标 1 中,我们将验证白色念珠菌 CAS5 调控的基因
IAC作为毒力决定因素,并鉴定其生物学功能。为了实现这些目标,我们将使用 RNA-Seq
对 cas5 无效突变体和 CAS5 重建菌株进行体外和时间转录分析
小鼠 IAC 期间的空间。然后,我们将通过以下方式验证某些 Cas5 调节基因作为毒力决定因素:
在 IAC 和 DC 小鼠模型中测试突变株,并表征其功能。在目标 2 中,我们将
使用类似的方法来验证 IAC 期间 RIM101 调节的基因作为毒力决定因素,并确定
他们的职能。在目标 3 中,我们将鉴定受白色念珠菌 CAS5 和 RIM101 调节的基因,以响应
IAC 期间使用米卡芬净,并验证其在棘白菌素耐药性或敏感性中的作用。我们将表演
白色念珠菌野生型 SC5314、cas5、rim101 和各自重构的 RNA-Seq 转录分析
菌株在体外和 IAC 期间对米卡芬净有反应,并验证某些基因对米卡芬净有贡献
体内反应。该项目将为棘白菌素和细胞壁应激反应提供新的见解。
与侵袭性念珠菌病的治疗和发病机制相关的白色念珠菌,并且具有潜力
以确定新的治疗和诊断目标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CORNELIUS J CLANCY其他文献
CORNELIUS J CLANCY的其他文献
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{{ truncateString('CORNELIUS J CLANCY', 18)}}的其他基金
Polyclonality of carbapenem resistant Enterobacteriaceae bloodstream infections
碳青霉烯类耐药肠杆菌科细菌血流感染的多克隆性
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- 批准号:
8112208 - 财政年份:2010
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