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

研究成果: ジャーナルへの寄稿記事

32 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)915-923
ページ数9
ジャーナルNature medicine
22
発行部数8
DOI
出版物ステータス出版済み - 8 1 2016
外部発表Yes

Fingerprint

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)

これを引用

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.

:: Nature medicine, 巻 22, 番号 8, 01.08.2016, p. 915-923.

研究成果: ジャーナルへの寄稿記事

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, 巻. 22, 番号 8, pp. 915-923. https://doi.org/10.1038/nm.4134
Wirnsberger G, Zwolanek F, Asaoka T, Kozieradzki I, Tortola L, Wimmer RA その他. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nature medicine. 2016 8 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. :: Nature medicine. 2016 ; 巻 22, 番号 8. pp. 915-923.
@article{73570529d04d410ea6e06393ae51ca73,
title = "Inhibition of CBLB protects from lethal Candida albicans sepsis",
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.",
author = "Gerald Wirnsberger and Florian Zwolanek and Tomoko Asaoka and Ivona Kozieradzki and Luigi Tortola and Wimmer, {Reiner A.} and Anoop Kavirayani and Friedrich Fresser and Gottfried Baier and Langdon, {Wallace Y.} and Fumiyo Ikeda and Karl Kuchler and Penninger, {Josef M.}",
year = "2016",
month = "8",
day = "1",
doi = "10.1038/nm.4134",
language = "English",
volume = "22",
pages = "915--923",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Inhibition of CBLB protects from lethal Candida albicans sepsis

AU - Wirnsberger, Gerald

AU - Zwolanek, Florian

AU - Asaoka, Tomoko

AU - Kozieradzki, Ivona

AU - Tortola, Luigi

AU - Wimmer, Reiner A.

AU - Kavirayani, Anoop

AU - Fresser, Friedrich

AU - Baier, Gottfried

AU - Langdon, Wallace Y.

AU - Ikeda, Fumiyo

AU - Kuchler, Karl

AU - Penninger, Josef M.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84978741609&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978741609&partnerID=8YFLogxK

U2 - 10.1038/nm.4134

DO - 10.1038/nm.4134

M3 - Article

C2 - 27428901

AN - SCOPUS:84978741609

VL - 22

SP - 915

EP - 923

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 8

ER -