Candida albicans triggers NLRP3-mediated pyroptosis in macrophages

Melanie Wellington; Kristy Koselny; Fayyaz S Sutterwala; Damian J Krysan

doi:10.1128/EC.00336-13

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Candida albicans triggers NLRP3-mediated pyroptosis in macrophages

Journal article

Open access

Peer reviewed

Candida albicans triggers NLRP3-mediated pyroptosis in macrophages

Melanie Wellington, Kristy Koselny, Fayyaz S Sutterwala and Damian J Krysan

Eukaryotic cell, Vol.13(2), pp.329-340

02/2014

DOI: 10.1128/EC.00336-13

PMCID: PMC3910967

PMID: 24376002

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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.

Candida albicans - pathogenicity

Caspase Inhibitors - pharmacology

Inflammasomes - metabolism

NLR Family, Pyrin Domain-Containing 3 Protein

Mice, Inbred C57BL

Cells, Cultured

Caspase 1 - metabolism

DNA Replication

Candida albicans - metabolism

Fungal Proteins - genetics

Candida albicans - genetics

Carrier Proteins - genetics

Macrophages - metabolism

Animals

Carrier Proteins - metabolism

Glycine - pharmacology

Cell Death

Trans-Activators - genetics

Macrophages - drug effects

Trans-Activators - metabolism

Mice

Mice, Inbred BALB C

Macrophages - microbiology

Fungal Proteins - metabolism

Details

Title: Subtitle: Candida albicans triggers NLRP3-mediated pyroptosis in macrophages
Creators: Melanie Wellington - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Kristy Koselny
Fayyaz S Sutterwala
Damian J Krysan
Resource Type: Journal article
Publication Details: Eukaryotic cell, Vol.13(2), pp.329-340
DOI: 10.1128/EC.00336-13
PMID: 24376002
PMCID: PMC3910967
NLM abbreviation: Eukaryot Cell
ISSN: 1535-9778
eISSN: 1535-9786
Publisher: American Society for Microbiology
Grant note: P30 ES005605 / NIEHS NIH HHS 1R01AI098450 / NIAID NIH HHS R01 AI098450 / NIAID NIH HHS R01 AI087630 / NIAID NIH HHS
Language: English
Date published: 02/2014
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093373602771

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