Requirement for Candida albicans Sun41 in Biofilm Formation and Virulence

Abstract

The cell wall of Candida albicans lies at the crossroads of pathogenicity and therapeutics. It contributes to pathogenicity through adherence and invasion; it is the target of both chemical and immunological antifungal strategies. We have initiated a dissection of cell wall function through targeted insertional mutagenesis of cell wall-related genes. Among 25 such genes, we were unable to generate homozygous mutations in 4, and they may be essential for viability. We created homozygous mutations in the remaining 21 genes. Insertion mutations in SUN41, Orf19.5412, Orf19.1277, MSB2, Orf19.3869, and WSC1 caused hypersensitivity to the cell wall inhibitor caspofungin, while two different ecm33 insertions caused mild caspofungin resistance. Insertion mutations in SUN41 and Orf19.5412 caused biofilm defects. Through analysis of homozygous sun41⌬/sun41⌬ deletion mutants and sun41⌬/sun41⌬؉pSUN41-complemented strains, we verified that Sun41 is required for biofilm formation and normal caspofungin tolerance. The sun41⌬/sun41⌬ mutant had altered expression of four cell wall damage response genes, thus suggesting that it suffers a cell wall structural defect. Sun41 is required for inducing disease, because the mutant was severely attenuated in mouse models of disseminated and oropharyngeal candidiasis. Although the mutant produced aberrant hyphae, it had no defect in damaging endothelial or epithelial cells, unlike many other hypha-defective mutants. We suggest that the sun41⌬/sun41⌬ cell wall defect is the primary cause of its attenuated virulence. As a small fungal surface protein with predicted glucosidase activity, Sun41 represents a promising therapeutic target.

Together we are strong—cell wall integrity sensors in yeasts

“…This will be of special interest for pathogenic fungi, such as some Candida species. Although similar signalling cascades are most likely involved in ensuring cell integrity in Candida albicans and Candida glabrata, and homologues to the S. cerevisiae CWI sensor genes can be found in the C. albicans genome, only CaWsc1 has so far been shown to increase the sensitivity towards Caspofungin [35,37]. To our knowledge, no detailed study of sensor functions has been presented for either Candida species or for the other model eukaryotic yeast, Schizosaccharomyces pombe.…”

Candida albicansCell Wall Proteins

“…The synthesis of this polysaccharide requires both cytoplasmic and cell wall activities, and its synthesis is not as well understood as are those of the other two structural polysaccharides (204,322). The null (kre9⌬/⌬) strain is inviable when grown on glucose (224,279). The mutant strain grows poorly on other carbon sources (224).…”

“…Four studies report defects associated with SUN41 deletion (103,138,279,390). Deletion of both alleles resulted in defects in hyphal formation, cell separation, and biofilm formation (103,138,279).…”

Retigeric Acid B Enhances the Efficacy of Azoles Combating the Virulence and Biofilm Formation of <i>Candida albicans</i>

“…Both kidneys were harvested, and one kidney was processed for histopathological analysis while the other was used for kidney fungal burden analysis as previously described. 15) The murine research methods were approved by Anminal Care and Use Commitee at Shandong University and followed the instructions to minimize the suffering of the mice.…”