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.

摘要 耳念珠菌是一种新出现的真菌病原体，可引起侵袭性，通常是多药耐药感染， 全球爆发。与许多其他真菌病原体不同，C.耳感染主要是医院感染， 由C.耳，以稳健地定殖医疗设备、植入物和非生物表面， 靠近病人区C.耳虱可以在非生物表面存活数周，许多菌株具有抵抗力。 通常使用的抗真菌剂和消毒剂，阻碍了净化工作。这一点的重要性 殖民地C.与减少听力相关的干预案例研究证明了耳疾病的传播 感染发生率与移走定植污染物。C.耳也可以在表面形成生物膜， 有助于其抵抗去污。在分子尺度上，这些过程需要最初的第一个 单个真菌细胞物理附着到表面的步骤。虽然对扣押的规定一直是 在相关真菌物种中进行了有限程度的探索，没有机制研究调查了分子生物学。 在C中控制初始附着的机械。耳。此外，C. auris编码的基因与 特征性的白色念珠菌ALS和IFF/HYR家族粘附素，这些蛋白质与 附着在其他真菌物种，我们的研究结果表明，这些基因都没有实质性贡献 附着在非生物表面的C.耳。相反，我们已经鉴定了B9J08_001458，一种新的粘附素 由C编码。没有特征性同源物的耳。B9J08_001458实质性缺失， 大大降低了C。耳粘连此外，我们的初步研究结果表明，自然转录 B9J08_001458在C.耳分离株与粘附力的自然变化有关。目标 本研究的目的是明确C.耳粘连并解释 不同C.耳临床分离株。我们的假设是C.耳调节 粘附细胞表面特征主要通过推定的新型粘附素B9J08_001458的表达， 这种粘附素的转录调控解释了C.耳分离物。 为了解决这个假设，我们将利用我们的全球遗传和转录组数据集来识别 靶向B9J08_001458的转录因子。我们的研究结果还表明，B9J08_001458通过以下途径调节： SWI/SNF染色质重塑复合物;我们将通过以下方式表征这一层的转录调控： 比较野生型细胞和SWI/SNF功能缺陷突变体之间的染色质状态。然后我们将 研究驱动B9J08_001458在不同C. 使用全基因组关联研究的auris分离物。这项提案的结果将提供一个科学的 为合理制定C.耳， 可能减轻这种真菌的疾病负担。