Inhibition of C. albicans filamentation by a C. glabrata biofilm-produced factor

光滑念珠菌生物膜产生因子对白色念珠菌丝状化的抑制

• 批准号: 8910045
• 负责人: Sabrina Patrice Martinez-Anz
• 金额: $ 3.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910045
• 关键词: 3-Dimensional; Acquired Immunodeficiency Syndrome; Adopted; Affect; Ammonium Sulfate; Antifungal Therapy; Area; Biochemical; Biological Assay; Cancer Patient; Candida; Candida albicans; Candida glabrata; Cells; Chromatography; Clinical; Complex; Data; Dental General Practice; Dentures; Development; Disease; Exclusion; Filament; Fungal Drug Resistance; Furuncles; Gene Targeting; Genitourinary system; Heating; High Pressure Liquid Chromatography; Hospitals; Human; Hydrophobic Interactions; Immunocompromised Host; Individual; Infection; Invaded; Ion Exchange; Laboratories; Lead; Lesion; Mass Spectrum Analysis; Microbial Biofilms; Modeling; Morphology; Mycoses; Oral; Oral candidiasis; Oral cavity; Oral health; Oral mucous membrane structure; Organism; Pathogenesis; Pathway interactions; Patients; Play; Population; Precipitation; Property; Proteins; Research; Research Personnel; Research Training; Role; Sepsis; Signal Transduction; Skin; Testing; United States; Virulence; Yeasts; attributable mortality; base; biophysical properties; design; effective therapy; gastrointestinal; improved; inhibitor/antagonist; insight; microbial community; novel; oral biofilm; oral cavity epithelium; oral fungal; oral lesion; oral tissue; pathogen; public health relevance; reconstitution; research study; response; therapeutic development; trait

 DESCRIPTION (provided by applicant): Candida species are the fourth leading cause of hospital-acquired bloodstream infections in the United States with an attributable mortality rate of 40-50%. Oral candidiasis is the most common fungal infection encountered in the general dental practice and immunocompromised individuals, including AIDS patients, are particularly susceptible. Candida albicans is the most frequently isolated species in oral thrush patients. C. albicans and C. glabrata are increasingly being co-isolated from fungal lesions in the oral cavity. C. albicans has the ability to undergo a morphological transition from single-celled yeast to hyphal filaments. This transition is required for virulence and plays an important role in the invasion of the oral mucosa as well as biofilm formation. Biofilms are complex microbial communities that are highly resistant to antifungal treatment and also important for the development and persistence of opportunistic yeast infections. Although C. glabrata does not readily form filaments, this species easily forms biofilms. While monospecies C. albicans biofilms have been well-studied, inter-Candida-species signaling interactions that affect filamentation, including filamentation in biofilms, are unknown. My preliminary data indicate that both C. albicans planktonic cells and biofilms are unable to form filaments in the presence of an established C. glabrata biofilm. Inhibition of C. albicans filamentation appears to occur in response to a secreted C. glabrata protein because complete inhibition is observed when C. albicans planktonic cells and biofilms are grown in the supernatant of an independently grown C. glabrata biofilm, the inhibitory activity is lost upon boiling the supernatant, and the inhibitoy factor can be precipitated from the supernatant by ammonium sulfate. Our laboratory has previously shown that constitutive high-level expression of UME6, a key filament-specific transcriptional regulator, is sufficient to generate a nearly complete filamentous population, driv increased biofilm formation and promote virulence. Interestingly, the factor produced by C. glabrata biofilms also completely inhibits C. albicans UME6-driven filamentation in both biofilms and planktonic cultures. Based on these results, my hypothesis is that the inhibitor of C. albicans filamentation produced by C. glabrata biofilms is a secreted factor that acts downstream of the UME6 pathway. In order to test this hypothesis, experiments in this proposal are designed to: 1) determine the identity of the C. glabrata biofilm-produced inhibitor of C. albicans filamentation, 2) determine the role that the C. glabrata biofilm-produced factor plays in inhibiting the virulence properties of a C. albicans UME6 expression strain as well as C. albicans clinical oral isolates. These studies are significant because the will provide important new insight into inter-Candida species signaling interactions that control filamentation of C. albicans, a major human oral fungal pathogen. Because of the important role that filamentation plays in C. albicans oral tissue invasion, biofilm formation, and pathogenesis, these studies are likely to provide information leading to the development of novel and more effective antifungal therapies to treat oral candidiasis.

 描述（由适用提供）：念珠菌物种是美国医院获得血液感染的第四个主要原因，可归因于40-50％的死亡率。口服念珠菌病是一般牙科实践中遇到的最常见的真菌感染，包括艾滋病患者在内的免疫功能低下的个体特别容易受到影响。白色念珠菌是口服鹅口疮患者中最常见的物种。白色念珠菌和glabrata越来越多地从口腔中的真菌病变中共隔离。 白色念珠菌具有从单细胞酵母到菌丝丝的形态学过渡。这种过渡是病毒所必需的，并且在侵袭口腔粘膜以及生物膜形成中起着重要作用。生物膜是复杂的微生物群落，对抗真菌治疗具有高度抗性，并且对于机会主义酵母菌感染的发展和持久性也很重要。尽管C. glabrata不容易形成细丝，但该物种很容易形成生物膜。虽然单身梭菌生物膜已经进行了充分研究，但影响细丝（包括生物膜中的细丝）的candida间种上的信号传导相互作用尚不清楚。我的初步数据表明，白色念珠菌浮游细胞和生物膜均无法在既定的Glabrata生物膜存在下形成细丝。当白色念珠菌蛋白蛋白质的抑制作用似乎发生在响应于白色念珠菌浮游细胞和生物膜的分泌的毛labrata蛋白中，而生物膜在一个独立的glabrata生物膜的上网中生长时，抑制性活性在沸腾的持续抑制因素时会因抑制性而损失，因此抑制性因素可能会因抑制性而损失。我们的实验室先前已经表明，主要细丝特异性转录调节剂UME6的本构高级表达足以产生几乎完整的丝状群体，DRIV增加了生物膜的形成并促进病毒。有趣的是，C. glabrata生物膜产生的因子也完全抑制白色念珠菌UME6驱动的细丝在生物膜和浮游培养基中。基于这些结果，我的假设是，白色念珠菌生物膜产生的白色念珠菌丝的抑制剂是作用于UME6途径下游的分泌因子。为了检验这一假设，该提案中的实验旨在：1）确定白色念珠菌丝状生物膜产生的生物膜生物膜生物膜生产的抑制剂的同一性，2）确定glabrata生物膜生物胶体生产因子在产生的作用的作用。 抑制白色念珠菌UME6表达菌株以及白色念珠菌临床口服分离株的病毒特性。这些研究很重要，因为该研究将为控制白色念珠菌的细丝（一种主要的人类口服真菌病原体的丝状丝化）提供重要的新见解。由于丝状在白色念珠菌口腔组织侵袭，生物膜形成和发病机理中起着重要作用，这些研究可能会提供信息，从而导致新型和更有效的抗真菌治疗疗法的治疗念珠菌病。