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The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation
Open accessAbstract
Although Candida glabrata is an important human pathogenic yeast, its pathogenicity mechanisms are largely unknown. Immune evasion strategies seem to play key roles during infection, since very little inflammation is observed in mouse models. Furthermore, C. glabrata multiplies intracellularly after engulfment by macrophages. In this study, we sought to identify the strategies that enable C. glabrata to survive phagosome biogenesis and antimicrobial activities within human monocyte-derived macrophages. We show that, despite significant intracellular proliferation, macrophage damage or apoptosis was not apparent, and production of reactive oxygen species was inhibited. Additionally, with the exception of GM-CSF, levels of pro- and anti-inflammatory cytokines were only marginally increased. We demonstrate that adhesion to and internalization by macrophages occur within minutes, and recruitment of endosomal early endosomal Ag 1 and lysosomal-associated membrane protein 1 indicates phagosome maturation. However, phagosomes containing viable C. glabrata, but not heat-killed yeasts, failed to recruit cathepsin D and were only weakly acidified. This inhibition of acidification did not require fungal viability, but it had a heat-sensitive surface attribute. Therefore, C. glabrata modifies the phagosome into a nonacidified environment and multiplies until the host cells finally lyse and release the fungi. Our results suggest persistence of C. glabrata within macrophages as a possible immune evasion strategy.
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In the citing paper
“Lastly, despite encountering iron restriction, ROS and carbon starvation, C. glabrata has equipped itself well with strategies to proliferate in macrophages, including transcriptional reconfiguration of cellular pathways [60,65,147].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [65]
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In the citing paper
“C. glabrata can be engulfed by macrophages, it is highly resistant to macrophage-mediated killing and can survive and proliferate within these host cells (16).”
From Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness (2023) · cites this paper as [16]
In the citing paper
“Of note, previous studies reported an ADY2a upregulation in C. glabrata cells upon macrophage phagocytosis (Kaur et al., 2007; Seider et al., 2011).”
From Candida glabrata susceptibility to antifungals and phagocytosis is modulated by acetate (2015) · cites this paper as Seider et al., 2011
In the citing paper
“The latter includes suppression of the production of pro-inflammatory cytokine IL-1β in human THP-1 macrophages, facilitating survival in macrophages and virulence in the models of murine systemic candidiasis and Drosophila melanogaster [58,60,65,66].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [65]
In the citing paper
“In accordance, macrophages did not produce TNF-α, IL-6, IL-8, IL-12, and IFN-γ pro-inflammatory cytokines, however, GM-CSF production has been reported upon C. glabrata infection [65].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [65]
In the citing paper
“In accordance, macrophages did not produce TNF-α, IL-6, IL-8, IL-12, and IFN-γ pro-inflammatory cytokines, however, GM-CSF production has been reported upon C. glabrata infection [65].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [65]
In the citing paper
“C. glabrata survives and replicates in human and murine macrophages without adversely affecting macrophages [60,65,147].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [65]
In the citing paper
“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 [65]
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Citations
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Metadata
- Authors
- Seider, K., Brunke, S., Schild, L., Jablonowski, N., Wilson, D., Majer, O., Barz, D., Haas, A., Kuchler, K., Schaller, M., & 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 Bonn (DE)
- University of Tübingen (DE)
- Corresponding author
- Seider, Katja
- Brunke, Sascha
- Schild, Lydia
- Jablonowski, Nadja
- Wilson, Duncan
- Hube, Bernhard
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09
- Volume
- 187
- Issue
- 6
- Pages
- 3072-3086
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2124863746
- Cited by
- 220
- References
- 80
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 15 · 2021: 18 · 2020: 23 · 2019: 18 · 2018: 16 · 2017: 8 · 2016: 14 · 2015: 20 · 2014: 16 · 2013: 16 · 2012: 6
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 670)
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Studienstiftung des Deutschen Volkes
- Center for Sepsis Control and Care
- 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 › Infectious Diseases › Fungal Infections and Studies
- Keywords
- Candida glabrata, immune evasion, cytokine production, reactive oxygen species, phagosome acidification, cathepsin D, LAMP1, GM-CSF, monocyte-derived macrophages, fungal virulence factors, host-pathogen interaction
- MeSH terms
- Candidiasis, Humans, Macrophages, Microscopy, Fluorescence, Phagosomes, Polymerase Chain Reaction, Cytokines, Apoptosis, Oligonucleotide Array Sequence Analysis, Candida glabrata, Microscopy, Electron, Transmission, Immune Evasion
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