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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 an 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 su, 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)., Peer Reviewed, Postprint (published version)

Vaginal candidiasis is an extremely common disease predominantly caused by four phylogenetically diverse species: Candida albicans; Candida glabrata; Candida parapsilosis; and Candida tropicalis. Using a time course infection model of vaginal epithelial cells and dual RNA sequencing, we show that these species exhibit distinct pathogenicity patterns, which are defined by highly species-specific transcriptional profiles during infection of vaginal epithelial cells. In contrast, host cells exhibit a homogeneous response to all species at the early stages of infection, which is characterized by sublethal mitochondrial signalling inducing a protective type I interferon response. At the later stages, the transcriptional response of the host diverges in a species-dependent manner. This divergence is primarily driven by the extent of epithelial damage elicited by species-specific mechanisms, such as secretion of the toxin candidalysin by C. albicans. Our results uncover a dynamic, biphasic response of vaginal epithelial cells to Candida species, which is characterized by protective mitochondria-associated type I interferon signalling and a species-specific damage-driven response., M.P., H.H., E.I., J.O.P., T.G., G.B. and B.H. received funding from the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant no. 642095 (OPATHY). B.H. also received support from the German Research Foundation within the Collaborative Research Centre/Transregio 124 FungiNet (project C1). M.S.G. was supported by the German Research Foundation Emmy Noether Programme (project no. 434385622/GR 5617/1-1). We acknowledge the support of the Spanish Ministry of Science, Innovation and Universities (grant no. PGC2018-099921-B-I00) to the European Molecular Biology Laboratory partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We thank C. Kämnitz from the Electron Microscopy Center in Jena for the sample preparation for TEM. The schematic models in Figs. 4–6 were created with images adapted from Servier Medical Art (Servier)., Peer Reviewed, Postprint (author's final draft)

Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients.