A Novel Immune Evasion Strategy of Candida albicans: Proteolytic Cleavage of a Salivary Antimicrobial Peptide

Abstract

Oropharyngeal candidiasis is an opportunistic infection considered to be a harbinger of AIDS. The etiologic agent Candida albicans is a fungal species commonly colonizing human mucosal surfaces. However, under conditions of immune dysfunction, colonizing C. albicans can become an opportunistic pathogen causing superficial or even life-threatening infections. The reasons behind this transition, however, are not clear. In the oral cavity, salivary antimicrobial peptides are considered to be an important part of the host innate defense system in the prevention of microbial colonization. Histatin-5 specifically has exhibited potent activity against C. albicans. Our previous studies have shown histatin-5 levels to be significantly reduced in the saliva of HIV+ individuals, indicating an important role for histatin-5 in keeping C. albicans in its commensal stage. The versatility in the pathogenic potential of C. albicans is the result of its ability to adapt through the regulation of virulence determinants, most notably of which are proteolytic enzymes (Saps), involved in tissue degradation. In this study, we show that C. albicans cells efficiently and rapidly degrade histatin-5, resulting in loss of its anti-candidal potency. In addition, we demonstrate that this cellular activity is due to proteolysis by a member of the secreted aspartic proteases (Sap) family involved in C. albicans pathogenesis. Specifically, the proteolysis was attributed to Sap9, in turn identifying histatin-5 as the first host-specific substrate for that isoenzyme. These findings demonstrate for the first time the ability of a specific C. albicans enzyme to degrade and deactivate a host antimicrobial peptide involved in the protection of the oral mucosa against C. albicans, thereby providing new insights into the factors directing the transition of C. albicans from commensal to pathogen, with important clinical implications for alternative therapy. This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV.

Design of a Novel Antimicrobial Peptide Activated by Virulent Proteases

“…It has been previously reported that proteases with such a substrate specificity degrade AMPs that are rich in positively charged and hydrophobic amino acids (26). As expected, the L-isomeric peptide was quickly degraded when mixed with Sap2 ( Figure S3).…”

Interplay between Candida albicans and the Antimicrobial Peptide Armory

“…Examples include the secretion of AMP-binding proteins that re- direct peptide antimicrobials away from microbial structures (52). As presented below, similar mechanisms were also shown for C. albicans (53)(54)(55)(56)(57)(58).…”

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

“…Both bacteria and fungi are inhibited by AMPs, but they can nevertheless survive if they contain defense mechanisms that limit AMP uptake (3) or inactivate AMPs, e.g., by proteases (4). In addition, microbes may secrete AMP binding proteins as decoys to lower effective AMP concentrations in their vicinity (5)(6)(7).…”