Human Antimicrobial Peptide LL-37 Inhibits Adhesion of Candida albicans by Interacting with Yeast Cell-Wall Carbohydrates

Abstract

Candida albicans is the major fungal pathogen of humans. Fungal adhesion to host cells is the first step of mucosal infiltration. Antimicrobial peptides play important roles in the initial mucosal defense against C. albicans infection. LL-37 is the only member of the human cathelicidin family of antimicrobial peptides and is commonly expressed in various tissues and cells, including epithelial cells of both the oral cavity and urogenital tract. We found that, at sufficiently low concentrations that do not kill the fungus, LL-37 was still able to reduce C. albicans infectivity by inhibiting C. albicans adhesion to plastic surfaces, oral epidermoid OECM-1 cells, and urinary bladders of female BALB/c mice. Moreover, LL-37-treated C. albicans floating cells that did not adhere to the underlying substratum aggregated as a consequence of LL-37 bound to the cell surfaces. According to the results of a competition assay, the inhibitory effects of LL-37 on cell adhesion and aggregation were mediated by its preferential binding to mannan, the main component of the C. albicans cell wall, and partially by its ability to bind chitin or glucan, which underlie the mannan layer. Therefore, targeting of cell-wall carbohydrates by LL-37 provides a new strategy to prevent C. albicans infection, and LL-37 is a useful, new tool to screen for other C. albicans components involved in adhesion.

Candida albicans Mucin Msb2 Is a Broad-Range Protectant against Antimicrobial Peptides

“…Thus, mammalian mucins and possibly other human glycostructures (38) may loosely bind or store AMPs, but they lack tight AMP binding activity (like C. albicans mucin Msb2*), because such activity could prevent release and accessibility of human AMPs, which would be counterproductive during microbial attack. MST technology may be used in the future to determine dissociation constants of AMPs with other body or microbial glycostructures (5)(6)(7)(38)(39)(40)(41)(42).…”

Interplay between Candida albicans and the Antimicrobial Peptide Armory

“…The C. albicans cell wall ␤-1,3-exoglucanase Xog1 has been identified as a LL-37 receptor (10). Xog1-LL-37 interactions led to cell wall remodeling, and Xog1 enzyme activity was elevated, lowering C. albicans adhesion (10,11). Subsequent to cleavage by a serine protease, processed forms of LL-37 were found at the human skin surface (KS-30 and RK-31) (12).…”

“…Recently, an Hst 5-spermidine conjugate has been developed, which enhanced fungicidal activity compared to nonconjugated Hst 5 (83). It is known that Hst 5 utilizes the polyamine transporters Dur3 and Dur31 for its uptake in C. albicans (16); therefore, the Hst 5 peptide (Hst 5 with amino acids 4 to 15 [Hst 5 [4][5][6][7][8][9][10][11][12][13][14][15] ]) conjugated with a GGG linker and spermidine was rapidly taken up, leading to higher in vitro and in vivo candicidal activity than with nonconjugated Hst 5 (83). Collectively, these results suggest that the development and investigation of AMP conjugates could lead to promising new antifungals.…”

Inactivation of the Antifungal and Immunomodulatory Properties of Human Cathelicidin LL-37 by Aspartic Proteases Produced by the Pathogenic Yeast Candida albicans

“…The main antibacterial functions of LL-37 disrupt the microbial cell membrane, which results in cytoplasm leakage (13). In infections with C. albicans, LL-37 can also reduce infectivity by inhibiting biofilm formation or yeast adhesion to the host cells (14). In addition to the direct microbicidal effects of LL-37, the peptide also indirectly influences the functions of the innate immune system, as well as adaptive immune responses, in order to combat invasive pathogens.…”