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

Research output: Contribution to journalArticle

32 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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C-Type Lectins
Candida
Candida albicans
Sepsis
Mycoses
Inflammasomes
Ubiquitin-Protein Ligases
Macrophages
Pathogens
Infection
Reactive Oxygen Species
Phosphotransferases
Chemical activation
Innate Immunity
Dendritic Cells
Peptides
Morbidity
Skin
mouse dectin-2
dectin 1

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

Inhibition of CBLB protects from lethal Candida albicans sepsis. / Wirnsberger, Gerald; Zwolanek, Florian; Asaoka, Tomoko; Kozieradzki, Ivona; Tortola, Luigi; Wimmer, Reiner A.; Kavirayani, Anoop; Fresser, Friedrich; Baier, Gottfried; Langdon, Wallace Y.; Ikeda, Fumiyo; Kuchler, Karl; Penninger, Josef M.

In: Nature medicine, Vol. 22, No. 8, 01.08.2016, p. 915-923.

Research output: Contribution to journalArticle

Wirnsberger, G, Zwolanek, F, Asaoka, T, Kozieradzki, I, Tortola, L, Wimmer, RA, Kavirayani, A, Fresser, F, Baier, G, Langdon, WY, Ikeda, F, Kuchler, K & Penninger, JM 2016, 'Inhibition of CBLB protects from lethal Candida albicans sepsis', Nature medicine, vol. 22, no. 8, pp. 915-923. https://doi.org/10.1038/nm.4134
Wirnsberger G, Zwolanek F, Asaoka T, Kozieradzki I, Tortola L, Wimmer RA et al. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nature medicine. 2016 Aug 1;22(8):915-923. https://doi.org/10.1038/nm.4134
Wirnsberger, Gerald ; Zwolanek, Florian ; Asaoka, Tomoko ; Kozieradzki, Ivona ; Tortola, Luigi ; Wimmer, Reiner A. ; Kavirayani, Anoop ; Fresser, Friedrich ; Baier, Gottfried ; Langdon, Wallace Y. ; Ikeda, Fumiyo ; Kuchler, Karl ; Penninger, Josef M. / Inhibition of CBLB protects from lethal Candida albicans sepsis. In: Nature medicine. 2016 ; Vol. 22, No. 8. pp. 915-923.
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