Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages
Open accessAbstract
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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Filamentation plays a key role in phagocytosis escape mediated through physical processes or by triggering NLRP3/caspase-1 inflammasome-dependent lysis.
“Among the known C. albicans virulence factors20, filamentation21 plays a key role in phagocytosis escape mediated through physical processes or by triggering NLRP3/caspase-1 inflammasome-dependent lysis22,23.”
From The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans (2021) · cites this paper as [23]
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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)
- 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
- 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
- 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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