Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells

Marina Pekmezovic, Ann-Kristin Kaune, Sophie Austermeier, Sophia U J Hitzler, Selene Mogavero, Hrant Hovhannisyan, Toni Gabaldón, Mark S Gresnigt* (Corresponding Author), Bernhard Hube* (Corresponding Author)

*Corresponding author for this work

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The opportunistic pathogen Candida glabrata is the second most frequent causative agent of vulvovaginal candidiasis (VVC), a disease that affects 70-75% of women at least once during their life. However, C. glabrata is almost avirulent in mice and normally incapable of inflicting damage to vaginal epithelial cells in vitro. We thus proposed that host factors present in vivo may influence C. glabrata pathogenicity. We, therefore, analyzed the impact of albumin, one of the most abundant proteins of the vaginal fluid. The presence of human, but not murine, albumin dramatically increased the potential of C. glabrata to damage vaginal epithelial cells. This effect depended on macropinocytosis-mediated epithelial uptake of albumin and subsequent proteolytic processing. The enhanced pathogenicity of C. glabrata can be explained by a combination of beneficial effects for the fungus, which includes increased access to iron, accelerated growth, and increased adhesion. Screening of C. glabrata deletion mutants revealed that Hap5, a key regulator of iron homeostasis, is essential for the albumin-augmented damage potential. The albumin-augmented pathogenicity was reversed by the addition of iron chelators and a similar increase in pathogenicity was shown by increasing the iron availability, confirming a key role of iron. Accelerated growth not only led to higher cell numbers, but also to increased fungal metabolic activity and oxidative stress resistance. Finally, the albumin-driven enhanced damage potential was associated with the expression of distinct C. glabrata virulence genes. Transcriptional responses of the epithelial cells suggested an unfolded protein response (UPR) and ER-stress responses combined with glucose starvation induced by fast growing C. glabrata cells as potential mechanisms by which cytotoxicity is mediated.Collectively, we demonstrate that albumin augments the pathogenic potential of C. glabrata during interaction with vaginal epithelial cells. This suggests a role for albumin as a key player in the pathogenesis of VVC.

Original languageEnglish
Article numbere1010037
Number of pages29
JournalPLoS Pathogens
Issue number10
Early online date28 Oct 2021
Publication statusPublished - 28 Oct 2021

Bibliographical note

Funding: M.P., H.H., T.G., and B.H. received funding from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 642095 (OPATHY). A.K. and B. H. received support from the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 812969 (FunHoMic). S.A. and B.H. were supported by funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 847507 (HDM-FUN). B.H. is further supported by the DFG within the Collaborative Research Centre (CRC)/Transregio (TRR) 124 “FungiNet” project C1 (DFG project number 210879364) and the Balance of the Microverse Cluster (Germany´s Excellence Strategy – EXC 2051 – Project-ID 390713860). M.S.G. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Emmy Noether Program (project no. 434385622 / GR 5617/1-1), and a Research Grant 2019 from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.P. and H.H. received salary from grant agreement No 642095 (OPATHY) (2016-2019). A.K. received salary from grant agreement No 812969 (FunHoMic) (2019-2022).

Data Availability Statement

All codes, packages and their versions are available at All transcriptome data analysis results, including figures and supplementary materials are fully reproducible using the scripts available at Raw sequencing data is submitted under project accession number PRJNA745548 to SRA database.


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