Abstract
Candida glabrata is an opportunistic human fungal pathogen that causes superficial mucosal and life-threatening bloodstream infections in immunocompromised individuals. Remodeling in cell wall components has been extensively exploited by fungal pathogens to adapt to host-derived stresses, as well as immune evasion. How this process contributes to C. glabrata pathogenicity is less understood. Here, we applied RNA sequencing and an in vivo invasive infection model to elucidate the prompt response of C. glabrata during infection. Fungal transcriptomes show a dramatic alteration in the expression of Srp1/Tip1-family cell wall structural proteins during systemic infection. Deletion of all six genes in this family (TIR2-5 and AWP6-7) that are upregulated during infection leads to a significantly lower fungal burden in organs, as well as an attenuated virulence in the dextran sulfate sodium-induced colitis model. The tir2-5 awp6-7 sextuple mutant does not display any defect in response to host-derived stresses. Rather, deletion of all these six genes results in a lower cell surface exposure of an adhesin Epa1, which could contribute to its reduced adhesion to epithelial cells and cytotoxicity, as well as attenuated virulence. Our study reveals that cell wall remodeling triggered by the alteration in the expression of structural proteins is a key virulence attribute in C. glabrata that facilitates this fungus adhering to host cells and persisting in organs.IMPORTANCECandida glabrata is one of the most frequent causes of candidiasis after Candida albicans. While C. albicans has been extensively studied, the mechanisms of infection and invasion of C. glabrata have not been fully elucidated. Using an infection model of systemic candidiasis and RNA sequencing, we show that there is a dramatic change in the expression of Srp1/Tip1-family genes during infection. Deletion of all six Srp1/Tip1-family genes that are upregulated during infection decreases the amount of cell wall-localized Epa1, probably reflecting the reduced adherence to epithelial cells and attenuated virulence in the sextuple mutant. These data suggest that alterations in the expression of Srp1/Tip1-family structural proteins trigger cell wall remodeling that increases the cell surface exposure of adhesins, such as Epa1, to promote virulence. Our study provides a pathogenic mechanism associated with C. glabrata in ensuring its sustenance and survival during infection.