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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的耳念珠菌是一种新兴的真菌病原体，可导致侵袭性、通常具有多重耐药性的感染和世界范围内爆发。与许多其他真菌病原体不同，耳念珠菌感染主要是医院内的、驱动的耳念珠菌倾向于在医疗设备、植入物和非生物表面上大量繁殖，这些设备靠近病人宿舍。耳念珠菌可以在非生物表面存活数周，并且许多菌株具有抗药性常用的抗真菌剂和消毒剂，阻碍了净化工作。这一点的重要性通过干预案例研究证明了耳念珠菌疾病传播的定植与减少相关清除定植污染物后的感染发生率。耳念珠菌也可能在表面形成生物膜有助于其抵抗去污的能力。在分子尺度上，这些过程需要首先单个真菌细胞物理附着到表面的步骤。虽然附件的规定已经在相关真菌物种中的探索程度有限，没有机制研究调查了分子控制耳念珠菌初始附着的机制。此外，虽然 C. auris 编码的基因与鉴定了白色念珠菌 ALS 和 IFF/HYR 家族粘附素，这些蛋白质与在其他真菌物种中的附着，我们的研究结果表明这些基因都没有实质上有助于耳念珠菌 (C. auris) 中非生物表面的附着。相反，我们发现了 B9J08_001458，一类新型粘附素由 C. auris 特异性编码，没有特征同源物。大幅删除 B9J08_001458 以及显着降低耳念珠菌粘附。此外，我们的初步研究结果表明自然转录耳念珠菌分离株中 B9J08_001458 的变异与粘附潜力的自然变异有关。目标该提案的目的是确定耳念珠菌粘附的功能和调节机制，并解释不同耳念珠菌临床分离株的粘附变异性。我们的假设是 C. auris 调节粘附细胞表面轮廓主要通过假定的新型粘附素 B9J08_001458 的表达，这种粘附素的转录控制解释了耳念珠菌分离株之间的粘附变异。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 是通过 SWI/SNF 染色质重塑复合物；我们将通过以下方式来表征这一层转录调控比较野生型细胞和 SWI/SNF 功能缺陷的突变体之间的染色质状态。我们随后将研究驱动 B9J08_001458 在不同 C. 中差异表达的遗传变异的影响。使用全基因组关联研究分离耳念珠菌。该提案的研究结果将为为合理制定针对耳念珠菌的净化和感染控制方案奠定了基础，有可能减轻这种真菌的疾病负担。