Requirement for Candida albicans Sun41 in biofilm formation and virulence.
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 sun41Delta/sun41Delta deletion mutants and sun41Delta/sun41Delta+pSUN41-complemented strains, we verified that Sun41 is required for biofilm formation and normal caspofungin tolerance. The sun41Delta/sun41Delta 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 sun41Delta/sun41Delta 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.
Norice
Carmelle T
CT
Department of Microbiology, Columbia University, New York, NY, USA.
Smith
Frank J
FJ
Solis
Norma
N
Filler
Scott G
SG
Mitchell
Aaron P
AP
D000818:Animals; D018441:Biofilms / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D002177:Candidiasis / Q000382:microbiology / Q000473:pathology; D000077336:Caspofungin; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D055666:Lipopeptides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D014774:Virulence / Q000187:drug effects
D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D000077336:Caspofungin