Molecular Mechanisms of Candida auris Adhesion to Abiotic Surfaces

耳念珠菌粘附非生物表面的分子机制

• 批准号: 10601671
• 负责人: Darian Jay Santana
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601671
• 关键词: Address; Adhesions; Adhesives; Antifungal Agents; Automobile Driving; Bacterial Adhesins; Candida albicans; Candida auris; Case Study; Cell surface; Cell-Matrix Junction; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Collection; Data Set; Decontamination; Development; Disease; Disease Outbreaks; Disinfectants; Excision; Family; Foundations; Gene Family; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Healthcare; Homologous Gene; Hospitals; Hydrophobic Surfaces; Implant; Incidence; Individual; Infection; Infection Control; Infection prevention; Intervention; Knowledge; Link; Measures; Mediating; Medical Device; Microbial Biofilms; Molecular; Multi-Drug Resistance; Outcome; Patients; Phenotype; Population; Predisposition; Process; Proteins; Protocols documentation; Regulation; Research; Resistance; Structure; Surface; Testing; Transcriptional Regulation; Variant; Virulence; burden of illness; cell type; design; differential expression; fungus; genetic variant; genome wide association study; member; molecular scale; mutant; novel; overexpression; pathogenic fungus; prevention practice; resistant strain; transcription factor; transcriptomics; transmission process

Abstract Candida auris is an emerging fungal pathogen responsible for invasive, often multidrug-resistant infections and outbreaks worldwide. Unlike for many other fungal pathogens, C. auris infection is primarily nosocomial, driven by the propensity of C. auris to robustly colonize medical devices, implants, and abiotic surfaces that are proximal to patient quarters. C. auris can survive on abiotic surfaces for weeks, and many strains are resistant to commonly used antifungals and disinfectants, hindering decontamination efforts. The importance of this colonization to C. auris disease spread is demonstrated by intervention case studies associating reduction of infection incidence with removal of colonized fomites. C. auris can also form biofilms on surfaces, likely contributing to its resistance to decontamination. On a molecular scale, these processes require the initial first step of individual fungal cells physically attaching to a surface. While the regulation of attachment has been explored to a limited extent in related fungal species, no mechanistic studies have investigated the molecular machinery governing initial attachment in C. auris. Furthermore, while C. auris encodes genes homologous to characterized Candida albicans ALS and IFF/HYR family adhesins, proteins which have been implicated in attachment in other fungal species, our findings indicate none of these genes substantially contributes to attachment to abiotic surfaces in C. auris. Instead, we have identified B9J08_001458, a novel class of adhesin specifically encoded by C. auris with no characterized homologs. Deletion of B9J08_001458 substantially and significantly reduces C. auris adhesion. Furthermore, our preliminary findings suggest natural transcriptional variation of B9J08_001458 among C. auris isolates is linked to natural variation in adhesive potential. The goal of this proposal is to identify the functional and regulatory mechanisms of C. auris adhesion and explain the variability in adhesion in different C. auris clinical isolates. Our hypothesis is that C. auris regulates an adhesive cell surface profile primarily through expression of the putative novel adhesin B9J08_001458, and that transcriptional control of this adhesin explains adhesive variation amongst C. auris isolates. To address this hypothesis, we will leverage our global genetic and transcriptomic datasets to identify transcription factors targeting B9J08_001458. Our findings also suggest B9J08_001458 is regulated through the SWI/SNF chromatin remodeling complex; we will characterize this layer of transcriptional regulation by comparing chromatin states between wild type cells and mutants deficient in SWI/SNF function. We will then investigate the impact of genetic variants driving differential expression of B9J08_001458 amongst diverse C. auris isolates using genome wide association studies. The findings of this proposal will provide a scientific foundation for the rational development of decontamination and infection control protocols against C. auris, potentially mitigating the disease burden of this fungus.

抽象的 念珠菌Auris是一种新兴的真菌病原体，负责侵入性，通常是多药的感染和 全球爆发。与许多其他真菌病原体不同，Auris C. Auris感染主要是医院的，驱动的 通过C. auris的倾向，可牢固地定居医疗设备，植入物和非生物表面 靠近患者区域。 C. auris可以在非生物表面生存数周，许多菌株具有抗性 对于常用的抗真菌性和消毒剂，阻碍了净化工作。这一点的重要性 通过干预案例研究与减少的干预案例研究证明了与奥里斯氏菌疾病蔓延的殖民化。 感染发生率，去除定殖的富米特人。 C. Auris也可以在表面上形成生物膜，可能 有助于其抵抗净化。在分子尺度上，这些过程需要首先 单个真菌细胞物理附着在表面上的步骤。虽然依恋的调节已经 在相关真菌物种中探索的程度有限，没有机械研究研究了分子 c. auris中的初始附件的机械。此外，C。Auris编码与 表征白色念珠菌ALS和IFF/HYR家族粘附素，与之相关的蛋白质 在其他真菌物种中的附着，我们的发现表明，这些基因均未实质上有助于 c。c.auris中的非生物表面的附着。相反，我们已经确定了B9J08_001458，这是一种新颖的粘合剂类 由C. auris特别编码，没有表征同源物。删除B9J08_001458的删除 明显降低了圆梭菌的粘附。此外，我们的初步发现表明自然转录 C. Auris分离株中B9J08_001458的变化与粘合剂潜力的自然变化有关。目标 该建议的是确定甲状腺梭菌粘附的功能和调节机制，并解释 不同C. auris临床分离株的粘附变异性。我们的假设是C. auris调节 粘合性细胞表面曲线主要是通过推定的新型粘附素B9J08_001458的表达 对这种粘附素的转录控制解释了C. auris分离株之间的粘附变化。 为了解决这一假设，我们将利用我们的全球遗传和转录组数据集识别 针对B9J08_001458的转录因子。我们的发现还表明B9J08_001458通过 SWI/SNF染色质重塑复合物；我们将通过 比较野生型细胞和突变体之间缺乏SWI/SNF功能的突变体。然后我们会 研究驱动B9J08_001458差异表达的遗传变异的影响。 使用基因组广泛关联研究的Auris分离株。该提案的发现将提供科学的 净化和感染控制方案的理性发展基础，针对Auris， 可能减轻这种真菌的疾病负担。