Candida albicans is a microbial fungus that exists as a commensal member of the human microbiome and an opportunistic pathogen. Cell surface-associated adhesin proteins play a crucial role in C. albicans' ability to undergo cellular morphogenesis, develop robust biofilms, colonize, and cause infection in a host. However, a comprehensive analysis of the role and relationships between these adhesins has not been explored. We previously established a CRISPR-based platform for efficient generation of single- and double-gene deletions in C. albicans, which was used to construct a library of 144 mutants, comprising 12 unique adhesin genes deleted singly, or in every possible combination of double deletions. Here, we exploit this adhesin mutant library to explore the role of adhesin proteins in C. albicans virulence. We perform a comprehensive, high-throughput screen of this library, using Caenorhabditis elegans as a simplified model host system, which identified mutants critical for virulence and significant genetic interactions. We perform follow-up analysis to assess the ability of high- and low-virulence strains to undergo cellular morphogenesis and form biofilms in vitro, as well as to colonize the C. elegans host. We further perform genetic interaction analysis to identify novel significant negative genetic interactions between adhesin mutants, whereby combinatorial perturbation of these genes significantly impairs virulence, more than expected based on virulence of the single mutant constituent strains. Together, this yields important new insight into the role of adhesins, singly and in combinations, in mediating diverse facets of virulence of this critical fungal pathogen.

中文翻译：

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白念珠菌毒力中粘附素的系统表征和遗传相互作用分析

白色念珠菌是一种微生物真菌，作为人类微生物组的常见成员和机会病原体而存在。细胞表面相关的粘附素蛋白在白色念珠菌经历细胞形态发生，形成坚固的生物膜，定居并引起宿主感染的能力中起着至关重要的作用。但是，尚未探索对这些粘附素之间的作用和关系的全面分析。我们之前建立了一个基于CRISPR的平台来有效地在白色念珠菌中产生单基因和双基因缺失，该平台用于构建144个突变体的文库，该突变体包含单个缺失的12个独特黏附素基因，或者以两种可能的组合缺失删除。在这里，我们利用这个粘附素突变体文库来探索粘附素蛋白在白色念珠菌毒力中的作用。我们执行全面，使用秀丽隐杆线虫（Caenorhabditis elegans）作为简化的模型宿主系统对该库进行高通量筛选，该系统鉴定了对毒力和重要遗传相互作用至关重要的突变体。我们进行后续分析，以评估高毒力和低毒力菌株在体外进行细胞形态发生和形成生物膜的能力，以及对线虫宿主的定殖。我们进一步进行遗传相互作用分析，以识别粘附素突变体之间的新型显着负遗传相互作用，从而这些基因的组合扰动显着削弱了毒力，超过了基于单个突变体组成菌株的毒力所预期的水平。在一起，这产生了重要的新见解，对黏附素在介导这种关键真菌病原体的多种毒力方面的作用（单独或组合使用）具有重要意义。