The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes.
Lydia KasperAnnika KönigPaul-Albert KoenigMark S GresnigtJohannes WestmanRebecca A DrummondMichail S LionakisOlaf GroßJuergen RulandJulian R NaglikBernhard HubePublished in: Nature communications (2018)
Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae.
Keyphrases
- nlrp inflammasome
- candida albicans
- cell death
- dendritic cells
- biofilm formation
- immune response
- escherichia coli
- oxidative stress
- endothelial cells
- cell cycle arrest
- peripheral blood
- blood glucose
- high glucose
- diabetic rats
- single cell
- copy number
- cell therapy
- metabolic syndrome
- type diabetes
- stem cells
- gram negative
- insulin resistance
- cell proliferation
- induced pluripotent stem cells
- induced apoptosis
- dna methylation
- transcription factor
- genome wide
- staphylococcus aureus
- mesenchymal stem cells
- case control
- genome wide identification
- pseudomonas aeruginosa
- natural killer cells