Fluidic Force Microscopy Demonstrates That Homophilic Adhesion by Candida albicans Als Proteins Is Mediated by Amyloid Bonds between Cells

• Published in: Nano letters 2019-06, Vol.19 (6), p.3846-3853
• Main Authors: Dehullu, Jérôme, Valotteau, Claire, Herman-Bausier, Philippe, Garcia-Sherman, Melissa, Mittelviefhaus, Maximilian, Vorholt, Julia A, Lipke, Peter N, Dufrêne, Yves F
• Format: Article
• Language: English
• Subjects: Amyloid - metabolism; Biofilms; Candida albicans - cytology; Candida albicans - physiology; Candidiasis - microbiology; Cell Adhesion; Cell Adhesion Molecules - metabolism; Equipment Design; Fungal Proteins - metabolism; Humans; Microscopy, Atomic Force - instrumentation; Single-Cell Analysis
• ISSN: 1530-6984; 1530-6992; 1530-6992
• DOI: 10.1021/acs.nanolett.9b01010

The fungal pathogen Candida albicans frequently forms drug-resistant biofilms in hospital settings and in chronic disease patients. Cell adhesion and biofilm formation involve a family of cell surface Als (agglutinin-like sequence) proteins. It is now well documented that amyloid-like clusters of laterally arranged Als proteins activate cell–cell adhesion under mechanical stress, but whether amyloid-like bonds form between aggregating cells is not known. To address this issue, we measure the forces driving Als5-mediated intercellular adhesion using an innovative fluidic force microscopy platform. Strong cell–cell adhesion is dependent on expression of amyloid-forming Als5 at high cell surface density and is inhibited by a short antiamyloid peptide. Furthermore, there is greatly attenuated binding between cells expressing amyloid-forming Als5 and cells with a nonamyloid form of Als5. Thus, homophilic bonding between Als5 proteins on adhering cells is the major mode of fungal aggregation, rather than protein–ligand interactions. These results point to a model whereby amyloid-like β-sheet interactions play a dual role in cell–cell adhesion, that is, in formation of adhesin nanoclusters (cis-interactions) and in homophilic bonding between amyloid sequences on opposing cells (trans-interactions). Because potential amyloid-forming sequences are found in many microbial adhesins, we speculate that this novel mechanism of amyloid-based homophilic adhesion might be widespread and could represent an interesting target for treating biofilm-associated infections.