SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans

Abstract

Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptideresistant strain of C. albicans, 36082 R , is hypervirulent in animal models versus its susceptible counterpart (36082 S ). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082 S and 36082 R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082 R than in 36082 S . In isogenic backgrounds, ssd1⌬/ssd1⌬ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1⌬/ssd1⌬ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.

Interplay between Candida albicans and the Antimicrobial Peptide Armory

“…Some response pathways, which mediate basal resistance to host defense peptides, are distinct from general stress adaptation. The C. albicans RNA-binding protein Ssd1, a component of the RAM (regulation of Ace2 and morphogenesis) pathway, and its downstream transcription factor Bcr1 desensitize susceptibility to AMPs by maintaining mitochondrial integrity and by reducing membrane permeabilization (57,64). Thus, ssd1 mutants were significantly more susceptible to AMPs.…”

Budding YeastSSD1-VRegulates Transcript Levels of Many Longevity Genes and Extends Chronological Life Span in Purified Quiescent Cells

“…One possible explanation is that SSD1-V, which encodes the full-length "wildtype" protein, reduces the virulence of Saccharomyces cerevisiae in one mouse model (Wheeler et al, 2003), but SSD1-V is critical in Candida (Gank et al, 2008) and several fungal pathogens of plants for evading their hosts' defense systems (Tanaka et al, 2007). In most cases, genetic interactions with SSD1-V are positive, whereas the premature termination alleles (ssd1-d) cause lethality or a more extreme phenotype.…”

Transcriptional Responses of Candida albicans to Epithelial and Endothelial Cells

“…Our finding that three of the genes that were upregulated in response to either epithelial or endothelial cells were required for C. albicans to resist antimicrobial peptides suggests that contact with these host cells induces a protective reaction that enables C. albicans to withstand these peptides. The capacity to tolerate antimicrobial peptides is important for C. albicans virulence because the extent of antimicrobial peptide resistance is directly related to virulence in animal models of disseminated candidiasis (22,76).…”