Inhibition of CBLB protects from lethal Candida albicans sepsis

Gerald Wirnsberger, Florian Zwolanek, Tomoko Asaoka, Ivona Kozieradzki, Luigi Tortola, Reiner A. Wimmer, Anoop Kavirayani, Friedrich Fresser, Gottfried Baier, Wallace Y. Langdon, Fumiyo Ikeda, Karl Kuchler, Josef M. Penninger

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40 Citations (Scopus)

Abstract

Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-Type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

Original languageEnglish
Pages (from-to)915-923
Number of pages9
JournalNature medicine
Volume22
Issue number8
DOIs
Publication statusPublished - Aug 1 2016
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wirnsberger, G., Zwolanek, F., Asaoka, T., Kozieradzki, I., Tortola, L., Wimmer, R. A., ... Penninger, J. M. (2016). Inhibition of CBLB protects from lethal Candida albicans sepsis. Nature medicine, 22(8), 915-923. https://doi.org/10.1038/nm.4134