Cited by 227Inflammasome and immune disordersAntifungal resistance and susceptibilityImmune Response and Inflammation

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Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

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Wellington, Melanie, Koselny, Kristy, Sutterwala, Fayyaz S., Krysan, Damian J.·2014·Eukaryotic Cell

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Abstract

Pyroptosis is an inflammasome-mediated programmed cell death pathway triggered in macrophages by a variety of stimuli, including intracellular bacterial pathogens. Activation of pyroptosis leads to the secretion of interleukin-1β (IL-1β) and pore-mediated cell lysis. Although not considered an intracellular pathogen, Candida albicans is able to kill and, thereby, escape from macrophages. Here, we show that C. albicans-infected bone marrow-derived macrophages (BMDM) and murine J774 macrophages undergo pyroptotic cell death that is suppressed by glycine and pharmacologic inhibition of caspase-1. Infection of BMDM harvested from mice lacking components of the inflammasome revealed that pyroptosis was dependent on caspase-1, ASC, and NLRP3 and independent of NLRC4. In contrast to its role during intracellular bacterial infection, pyroptosis does not restrict C. albicans replication. Nonfilamentous Candida spp. did not trigger pyroptosis, while Candida krusei, which forms pseudohyphae in macrophages, triggered much lower levels than did C. albicans. Interestingly, a Saccharomyces cerevisiae strain from the filamentous background Σ1278 also triggered low, but significant, levels of pyroptosis. We have found that deletion of the transcription factor UPC2 decreases pyroptosis but has little effect on filamentation in the macrophage. In addition, a gain-of-function mutant of UPC2 induces higher levels of pyroptosis than does a matched control strain. Taken together, these data are most consistent with a model in which filamentation is necessary but not sufficient to trigger NLRP3 inflammasome-mediated pyroptosis. This is the first example of a fungal pathogen triggering pyroptosis and indicates that C. albicans-mediated macrophage damage is not solely due to hypha-induced physical disruption of cellular integrity.

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Authors: Wellington, M., Koselny, K., Sutterwala, F. S., & Krysan, D. J.
Affiliations: University of Rochester Medicine (US)
University of Iowa (US)
ORCID: Wellington, Melanie
Sutterwala, Fayyaz S.
Krysan, Damian J.
Venue: Eukaryotic Cell
Publisher: American Society for Microbiology
Published: 2014-02
Volume: 13
Issue: 2
Pages: 329-340
ISSN: 1535-9778 (ISSN-L)
1535-9786
DOI: 10.1128/ec.00336-13
PMC: PMC3910967
OpenAlex: W2117231363
Cited by: 227
References: 49
Citations by year: 2026: 16 · 2025: 10 · 2024: 9 · 2023: 18 · 2022: 18 · 2021: 22 · 2020: 25 · 2019: 19 · 2018: 26 · 2017: 19 · 2016: 16 · 2015: 19 · 2014: 10
FWCI: 6.72
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Eukaryotic Cell (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Medical Center, University of Rochester
National Institute of Allergy and Infectious Diseases (R01AI087630, R01AI098450)
National Institute of Environmental Health Sciences (P30ES005605)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: Candida albicans, pyroptosis, NLRP3 inflammasome, macrophages, caspase-1, ASC, NLRC4, fungal pathogens, filamentation, pseudohyphae, Candida krusei, Saccharomyces cerevisiae, UPC2, IL-1β, bone marrow-derived macrophages, programmed cell death
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Candida albicans, Carrier Proteins, Cells, Cultured, DNA Replication, Fungal Proteins, Glycine, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Trans-Activators, Cell Death, Caspase 1, Mice, Inflammasomes, Caspase Inhibitors

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Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

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