An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans.
Candida albicans is an opportunistic fungal pathogen causing life-threatening mucosal and systemic infections in immunocompromised humans. Using a murine model of mucosal Candida infection, we investigated the role of the proinflammatory cytokine IL-1beta in host defense to Candida albicans. We find that the synthesis, processing, and release of IL-1beta in response to Candida are tightly controlled and first require transcriptional induction, followed by a second signal leading to caspase-1-mediated cleavage of the pro-IL-1beta cytokine. The known fungal pattern recognition receptors TLR2 and Dectin-1 regulate IL-1beta gene transcription, whereas the NLRP3-containing proinflammatory multiprotein complex, the NLRP3 inflammasome, controls caspase-1-mediated cleavage of pro-IL-1beta. Furthermore, we show that TLR2, Dectin-1, and NLRP3 are essential for defense against dissemination of mucosal infection and mortality in vivo. Therefore, in addition to sensing bacterial and viral pathogens, the NLRP3 inflammasome senses fungal pathogens and is critical in host defense against Candida.
Hise
Amy G
AG
Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA. amy.hise@case.edu
Tomalka
Jeffrey
J
Ganesan
Sandhya
S
Patel
Krupen
K
Hall
Brian A
BA
Brown
Gordon D
GD
Fitzgerald
Katherine A
KA
D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020170:Caspase 1