TY - JOUR
T1 - The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes
AU - Kasper, Lydia
AU - König, Annika
AU - Koenig, Paul Albert
AU - Gresnigt, Mark S.
AU - Westman, Johannes
AU - Drummond, Rebecca A.
AU - Lionakis, Michail S.
AU - Groß, Olaf
AU - Ruland, Jürgen
AU - Naglik, Julian R.
AU - Hube, Bernhard
PY - 2018/12/15
Y1 - 2018/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054893042&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06607-1
DO - 10.1038/s41467-018-06607-1
M3 - Article
C2 - 30323213
AN - SCOPUS:85054893042
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4260
ER -