Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

Authors

  • Donatella Pietrella,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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    • These authors contributed equally to this work.

  • Neelam Pandey,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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    • These authors contributed equally to this work.

  • Elena Gabrielli,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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  • Eva Pericolini,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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  • Stefano Perito,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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  • Lydia Kasper,

    1. Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany
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  • Francesco Bistoni,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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  • Antonio Cassone,

    1. Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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  • Bernhard Hube,

    1. Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany
    2. Friedrich Schiller University, Jena, Germany
    3. Center for Sepsis Control and Care (CSCC), Jena, Germany
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  • Anna Vecchiarelli

    Corresponding author
    • Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
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Full correspondence Dr. Anna Vecchiarelli, Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06126 Perugia, Italy

Fax: +39-075-585-7407

e-mail: vecchiar@unipg.it

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.

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