Identification of 10 genes on Candida albicans chromosome 5 that control surface exposure of the immunogenic cell wall epitope β-glucan and cell wall remodeling in caspofungin-adapted mutants

Abstract

ABSTRACT Candida albicans is part of normal microbiota; however, it can cause superficial and life-threatening infections in immune-compromised individuals. As the use of drugs from the echinocandin (ECN) class for the treatment of candidiasis is increasing, resistance against ECNs is also emerging. We identified 10 genes on C. albicans chromosome 5 (Ch5) that are simultaneously downregulated to decrease susceptibility to ECN caspofungin. Independent knock-out experiments demonstrated that these genes act overall to decrease the 1,3-β-glucan level in the cell wall, change levels of mannan and chitin, and affect expression of FKS genes. Importantly, 10 genes on Ch5 increase or decrease surface exposure of the immunogenic epitope 1,3-β-glucan. Our data indicate functions for previously uncharacterized orf19.970 and orf19.4149.1, of which orf19.970 has no human ortholog. Our data also indicate new functions for the genes DUS4, RPS25B, UAP1, URA7, RPO26, HAS1, and CKS1, whereas the function of CHT2 as a negative regulator of ECN susceptibility has been previously established. Importantly, half of the above genes are essential; hence, indispensable processes are involved in the adaptation to ECNs. Our results suggest that a novel group of genes works in concert to control adaptation to ECNs and point to potential new drug targets. IMPORTANCE Candida infections are often fatal in immuno-compromised individuals, resulting in many thousands of deaths per year. Caspofungin has proven to be an excellent anti-Candida drug and is now the frontline treatment for infections. However, as expected, the number of resistant cases is increasing; therefore, new treatment modalities are needed. We are determining metabolic pathways leading to decreased drug susceptibility in order to identify mechanisms facilitating evolution of clinical resistance. This study expands the understanding of genes that modulate drug susceptibility and reveals new targets for the development of novel antifungal drugs.

Keywords

• Candida albicans
• caspofungin adaptation
• cell wall remodeling
• 1,3-β-glucan exposure
• chromosome 5 genes