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

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 e...

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Autores principales:	Marina Pekmezovic, Ann-Kristin Kaune, Sophie Austermeier, Sophia U J Hitzler, Selene Mogavero, Hrant Hovhannisyan, Toni Gabaldón, Mark S Gresnigt, Bernhard Hube
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/572684198c1742e8b04dff63f55504d9
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spelling	oai:doaj.org-article:572684198c1742e8b04dff63f55504d92021-12-02T19:59:58ZHuman albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.1553-73661553-737410.1371/journal.ppat.1010037https://doaj.org/article/572684198c1742e8b04dff63f55504d92021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1010037https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The 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 suggests a role for albumin as a key player in the pathogenesis of VVC.Marina PekmezovicAnn-Kristin KauneSophie AustermeierSophia U J HitzlerSelene MogaveroHrant HovhannisyanToni GabaldónMark S GresnigtBernhard HubePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1010037 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Marina Pekmezovic Ann-Kristin Kaune Sophie Austermeier Sophia U J Hitzler Selene Mogavero Hrant Hovhannisyan Toni Gabaldón Mark S Gresnigt Bernhard Hube Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
description	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 suggests a role for albumin as a key player in the pathogenesis of VVC.
format	article
author	Marina Pekmezovic Ann-Kristin Kaune Sophie Austermeier Sophia U J Hitzler Selene Mogavero Hrant Hovhannisyan Toni Gabaldón Mark S Gresnigt Bernhard Hube
author_facet	Marina Pekmezovic Ann-Kristin Kaune Sophie Austermeier Sophia U J Hitzler Selene Mogavero Hrant Hovhannisyan Toni Gabaldón Mark S Gresnigt Bernhard Hube
author_sort	Marina Pekmezovic
title	Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
title_short	Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
title_full	Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
title_fullStr	Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
title_full_unstemmed	Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.
title_sort	human albumin enhances the pathogenic potential of candida glabrata on vaginal epithelial cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/572684198c1742e8b04dff63f55504d9
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Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells.

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