title: Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome.
abstract: In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL-1β and IL-18 production through inflammasome activation. This occurs via NLRP3 and caspase-1 activation, which cleaves pro-IL-1β into secreted bioactive IL-1β, a cytokine that was induced by Saps in monocytes, in monocyte-derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL-1β. Inflammasome activation required Sap internalization via a clathrin-dependent mechanism, intracellular induction of K(+) efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS-ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity.
authors.affiliation: Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Pietrella
authors.forename: Neelam
authors.initials: N
authors.lastname: Pandey
authors.forename: Elena
authors.initials: E
authors.lastname: Gabrielli
authors.forename: Eva
authors.initials: E
authors.lastname: Pericolini
authors.forename: Stefano
authors.initials: S
authors.lastname: Perito
authors.forename: Lydia
authors.initials: L
authors.lastname: Kasper
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Antonio
authors.initials: A
authors.lastname: Cassone
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hube
authors.forename: Anna
authors.initials: A
authors.lastname: Vecchiarelli
mesh_terms: D057055:Aspartic Acid Proteases / Q000378:metabolism*; D002176:Candida albicans / Q000201:enzymology* / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D013481:Superoxides; D057055:Aspartic Acid Proteases; D011188:Potassium