Identification of Candida glabrata Genes Involved in pH Modulation and Modification of the Phagosomal Environment in Macrophages
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Candida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.
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C. glabrata infection did not substantially activate any MAPK pathway including Erk1/2, SAPK/JNK, and NF-κB signaling.
“C. glabrata infection did not substantially activate any MAPK pathway including Erk1/2 (Extracellular signal-regulated kinases), SAPK/JNK (Stress-activated protein kinases/Jun amino-terminal kinases) and NF-κB signaling [149].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [149]
CgMnn10 and CgMnn11 have been implicated in ammonia extrusion-dependent environmental alkalinization.
“Of note, CgMnn10 and CgMnn11 have also been implicated in the ammonia extrusion-dependent environmental alkalinization which may partly account for their role in impeding phagolysosomal acidification [149].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [149]
CgVps15, CgVps34, CgMnn10, CgMnn11, CgLdb17, and CgSla2 contributed to the inhibition of phagolysosomal acidification.
“C. glabrata is also known to impede maturation of the phagosome in macrophages [65,147], and the phosphoinositide 3-kinase subunits (CgVps15 and CgVsps34), mannosyltransferases (CgMnn10 and CgMnn11) and vesicular trafficking proteins (CgLdb17 and CgSla2) contributed to the inhibition of phagolysosomal acidification [147,149,150].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [149]
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“…invasive strains isolated from host fluids – SAT02PL from peritoneal liquid, and SAT03BC from blood – present better growth in stress conditions (low pH and oxidative stress) that could be potentially related to higher survival rate in the phagolysosome of human macrophages (Kasper et al., 2014).”
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“Similar data were observed in other studies with other pathogens in which insufficient acidification of phagosomal environment facilitates Streptococcus pyogenes , Serratia marcescens , and Candida glabrata survival and growth in host cells (36–38).”
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“The distantly related pathogenic yeast Candida glabrata also inhibits phagosomal acidification in a process that depends on Golgi-localized α-mannosyl transferases (Kasper et al., 2014).”
BackgroundRasheed, M., Battu, A., & Kaur, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.813741 · Cited by 51 · see citing works
“glabrata cells has previously been shown to result in prolonged activation of the Syk pathway while having no effect on the NF- B pathway (49).”
BackgroundCharacterization of Virulence-Related Phenotypes in Candida Species of the CUG Clade
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Of mice, flies – and men? Comparing fungal infection models for large-scale screening efforts
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“Interestingly, one of the strongly reduced C. glabrata mutants in mice (and to a certain extent flies) – mnn10Δ – has recently been found to be important for survival in macrophages and has been implicated in active alkalization of the phagosome (Kasper et al., 2014).”
BackgroundSelf-citationVacuolar ATPase in phago(lyso)some biology
Kissing, S., Säftig, P., & Haas, A. (2017) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2017.08.007 · Cited by 47 · see citing works
Self-citation<i>Candida auris</i> —macrophage cellular interactions and transcriptional response
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“Under Pressure” – How fungi evade, exploit, and modulate cells of the innate immune system
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Self-citation<i>Candida glabrata</i> : new tools and technologies—expanding the toolkit
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“In addition, Kasper et al. (2014) utilized the deletion collection to identify genes required for environmental alkalinization and showed that protein mannosylation may play a key role in C. glabrata’s ability to alter the phagosomal environment allowing it to survive and proliferate…”
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Candida glabrata is a successful pathogen: An artist manipulating the immune response
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It takes a village: Phagocytes play a central role in fungal immunity
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Self-citationCandida glabrata: A Tale of Stealth and Endurance
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Suzuki, Y., Kami, D., Taya, T., Sano, A., Ogata, T., Matoba, S., & Gojo, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1089905 · Cited by 20 · see citing works
“A fungus ensures intracellular survival by alkalinizing lysosomal acidity (70), and it has been shown that attenuation of lysosome acidity reduces bactericidal activity against E.”
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“antifungal tolerance and macrophage survival (30, 31).”
Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway-
Taya, T., Teruyama, F., & Gojo, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1227467 · Cited by 14 · see citing works
Zajta, E., Csonka, K., Tóth, A., Tiszlavicz, L., Németh, T., Orosz, A., Novák, Á., Csikós, M., Vágvölgyi, C., Mócsai, A., et al. (2021) · mBio · doi:10.1128/mbio.01608-21 · Cited by 13 · see citing works
Host Sensing by Pathogenic Fungi
Sherrington, S. L., Kumwenda, P., Kousser, C., & Hall, R. A. (2017) · Advances in applied microbiology · doi:10.1016/bs.aambs.2017.10.004 · Cited by 13 · see citing works
RNAi as a Tool to Study Virulence in the Pathogenic Yeast Candida glabrata
Ishchuk, O. P., Ahmad, K. M., Koruza, K., Bojanovič, K., Sprenger, M., Kasper, L., Brunke, S., Hube, B., Säll, T., Hellmark, T., et al. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01679 · Cited by 12 · see citing works
“The direct acylation of macromolecules using aminoacyl-tRNA can change their activity, recognition or directs them to degradation (Katz et al., 2016).”
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Microbe Profile: Candida glabrata – a master of deception
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“A C. glabrata mutant screen uncovered mnn10 and mnn11 deletions that failed to prevent vacuole acidification in an ex vivo assay [27], suggesting that mannosyltransferases impact protein glycosylation and secretion, which aid in neutralization.”
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“glabrata have other adaptations to increase intracellular survival, and phagocytes may be an important reservoir for fungal persistence.(33,34) We previously observed that C.”
BackgroundDelfan, R. R., Fekrirad, Z., Nadoushan, M. J., & Rasooli, I. (2024) · Medicine in Microecology · doi:10.1016/j.medmic.2024.100113 · Cited by 8 · see citing works
Investigating Candida glabrata Urinary Tract Infections (UTIs) in Mice Using Bioluminescence Imaging
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Diverse mechanisms control amino acid‐dependent environmental alkalization by Candida albicans
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“The capacity to neutralize the environment in the presence of amino acids was reported previously in other members of the pathogenic Candida species complex (Vylkova et al., 2011), including the multi-drug resistant C. auris (Smith et al., 2022) and C. glabrata (Kasper et al., 2014).”
BackgroundInfluentialArastehfar, A. A., Daneshnia, F., Hovhannisyan, H., Cabrera, N., İlkit, M., Desai, J. V., Gabaldón, T., Shor, E., & Perlin, D. S. (2024) · FEMS Yeast Research · doi:10.1093/femsyr/foae035 · Cited by 6 · see citing works
Coronary Vasculitis Induced in Mice by the Cell Wall Mannoprotein of Candida krusei
Yanai, C., Hiroaki, T., Miura, N. N., Ishibashi, K., Yamanaka, D., Ohnishi, H., Ohno, N., & Adachi, Y. (2020) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b19-01060 · Cited by 6 · see citing works
Exploring protein derivative profiles in cheese whey through native Candida tropicalis fermentation
Utama, G. L., Utba, F., Sari, V. F., Nurmilah, S., Cahyana, Y., & Balia, R. L. (2024) · International Journal of Food Properties · doi:10.1080/10942912.2024.2317746 · Cited by 5 · see citing works
“[70] The growth of Candida spp. considerably slower with aromatic amino acids such as phenylalanine, tryptophan, tyrosine, and also histidine.”
Mannan is a context-dependent shield that modifies virulence in Nakaseomyces glabratus
Ribeiro, G. F., Priest, E. L., Heaney, H., Richardson, J. P., & Childers, D. S. (2025) · Virulence · doi:10.1080/21505594.2025.2491650 · Cited by 4 · see citing works
“In N. glabratus , mnn10 Δ cells exhibit reduced survival upon in vitro macrophage challenge compared to the wild-type strain [23].”
The thrips gut pH and implications for symbiont-mediated RNAi
Andongma, A. A., Whitten, M. M. A., Chofong, G. N., & Dyson, P. J. (2025) · Bulletin of Entomological Research · doi:10.1017/s0007485325000240 · Cited by 3 · see citing works
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Candida glabrata and the host: a neglected affair
Ghosh, M., Raney, M., & Kaur, R. (2026) · Journal of Medical Microbiology · doi:10.1099/jmm.0.002161 · Cited by 1 · see citing works
“The catalytic (CgVps34) and regulatory (CgVps15) subunits of the sole phosphoinositide 3-kinase (produces phosphatidylinositol 3-phosphate) and α -1,6-mannosyltransferases Mnn10 and Mnn11 have been shown to be important for impeding phagosome maturation [20–22].”
Characterization of the ATO Gene Family in Alternative Carbon Metabolism
Danhof, H. A. (2016) · Digital Commons-TMC (Texas Medical Center)
The NADPH oxidase-induced phagosomal environment of neutrophils and other phagocytes
Foote, J. R. (2019) · UCL Discovery (University College London)
Interactions Between Intracellular Fungal Pathogens and Host Phagocytes
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From confrontation to co-adaptation: the dynamic dialogue of Candida albicans and macrophages
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- Authors
- Kasper, L., Seider, K., Gerwien, F., Allert, S., Brunke, S., Schwarzmüller, T., Ames, L., Zubiria-Barrera, C., Mansour, M. K., Becken, U., Barz, D., Vyas, J. M., Reiling, N., Haas, A., Haynes, K., Kuchler, K., & Hube, B.
- Affiliations
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Jena University Hospital (DE)
- Max Perutz Labs (AT)
- University of Exeter (GB)
- Massachusetts General Hospital (US)
- Research Center Borstel - Leibniz Lung Center (DE)
- University of Bonn (DE)
- Corresponding author
- Hube, Bernhard
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-01
- Volume
- 9
- Issue
- 5
- Pages
- e96015
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4006850
- OpenAlex
- W2080201761
- Cited by
- 59
- References
- 64
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 2
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (097377/Z/11/Z, 097377, /Z/11/Z)
- Deutsche Forschungsgemeinschaft (SPP 1580, 528/15)
- Austrian Science Fund (I 746)
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BBS/B/10331, BB/H53146X/2, BB/F005210/2, BB/H53146X/1, BB/F005210/1)
- National Institute of Allergy and Infectious Diseases (R01AI092084, R01AI079198, K08AI110655)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida glabrata, phagosome acidification, phagosome maturation, macrophages, mannosyltransferase, Syk activation, V-ATPase, phagosome-lysosome fusion, invasive candidiasis, mutant screen
- MeSH terms
- Animals, Candidiasis, Cell Differentiation, Cell Line, Humans, Hydrogen-Ion Concentration, Lysosomes, Macrophage Activation, Macrophages, Phagosomes, Signal Transduction, Candida glabrata, Intracellular Space, Mice
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