Targeting CBLB as a potential therapeutic approach for disseminated candidiasis

Yun Xiao, Juan Tang, Hui Guo, Yixia Zhao, Rong Tang, Song Ouyang, Qiuming Zeng, Chad A. Rappleye, Murugesan V. S. Rajaram, Larry S. Schlesinger, Lijian Tao, Gordon D. Brown, Wallace Y. Langdon, Belinda T. Li, Jian Zhang

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Abstract

Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.

Original languageEnglish
Pages (from-to)906-914
Number of pages9
JournalNature Medicine
Volume22
Issue number8
Early online date18 Jul 2016
DOIs
Publication statusPublished - Aug 2016

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Candidiasis
Candida albicans
Innate Immunity
Pattern Recognition Receptors
Ubiquitin-Protein Ligases
Candida
Gene Silencing
Therapeutics
Infection
Blood
Phosphotransferases
Genes
Mortality
dectin 1
mouse dectin-2

Cite this

Xiao, Y., Tang, J., Guo, H., Zhao, Y., Tang, R., Ouyang, S., ... Zhang, J. (2016). Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nature Medicine, 22(8), 906-914. https://doi.org/10.1038/nm.4141

Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. / Xiao, Yun; Tang, Juan; Guo, Hui; Zhao, Yixia; Tang, Rong; Ouyang, Song; Zeng, Qiuming; Rappleye, Chad A.; Rajaram, Murugesan V. S.; Schlesinger, Larry S.; Tao, Lijian; Brown, Gordon D.; Langdon, Wallace Y.; Li, Belinda T.; Zhang, Jian.

In: Nature Medicine, Vol. 22, No. 8, 08.2016, p. 906-914.

Research output: Contribution to journalArticle

Xiao, Y, Tang, J, Guo, H, Zhao, Y, Tang, R, Ouyang, S, Zeng, Q, Rappleye, CA, Rajaram, MVS, Schlesinger, LS, Tao, L, Brown, GD, Langdon, WY, Li, BT & Zhang, J 2016, 'Targeting CBLB as a potential therapeutic approach for disseminated candidiasis', Nature Medicine, vol. 22, no. 8, pp. 906-914. https://doi.org/10.1038/nm.4141
Xiao, Yun ; Tang, Juan ; Guo, Hui ; Zhao, Yixia ; Tang, Rong ; Ouyang, Song ; Zeng, Qiuming ; Rappleye, Chad A. ; Rajaram, Murugesan V. S. ; Schlesinger, Larry S. ; Tao, Lijian ; Brown, Gordon D. ; Langdon, Wallace Y. ; Li, Belinda T. ; Zhang, Jian. / Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. In: Nature Medicine. 2016 ; Vol. 22, No. 8. pp. 906-914.
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abstract = "Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.",
author = "Yun Xiao and Juan Tang and Hui Guo and Yixia Zhao and Rong Tang and Song Ouyang and Qiuming Zeng and Rappleye, {Chad A.} and Rajaram, {Murugesan V. S.} and Schlesinger, {Larry S.} and Lijian Tao and Brown, {Gordon D.} and Langdon, {Wallace Y.} and Li, {Belinda T.} and Jian Zhang",
note = "We thank J.M. Penninger (University of Toronto) for providing Cblb−/− mice, Y. Iwakura (Tokyo University of Science) for providing Clec4n−/− mice, S. Lipkowitz (National Cancer Institute, US National Institutes of Health) for providing Cblb constructs, X. Lin (MD Anderson Cancer Center) for providing the antibody to mouse dectin-3 and Card9−/− bone marrow cells, P.R. Sundstrom (Dartmouth University) for providing the C. albicans cap1 mutant, and L.D. Chaves (University at Buffalo) for flow cytometric analysis of myeloid cells in the kidneys. We also thank A. Lovett-Racke (Ohio State University) for her advice on in vivo Cblb-knockdown experiments. This work was supported by the US National Institutes of Health (grants R01 AI090901, R01 AI123253, and R21 AI117547; all to J.Z.), the American Heart Association (AHA Great Rivers Associate Grant-in-Aid grant 16GRNT26990004; J.Z.), a start-up fund from the Ohio State University College of Medicine (J.Z.), and the Wellcome Trust (G.D.B.).",
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N1 - We thank J.M. Penninger (University of Toronto) for providing Cblb−/− mice, Y. Iwakura (Tokyo University of Science) for providing Clec4n−/− mice, S. Lipkowitz (National Cancer Institute, US National Institutes of Health) for providing Cblb constructs, X. Lin (MD Anderson Cancer Center) for providing the antibody to mouse dectin-3 and Card9−/− bone marrow cells, P.R. Sundstrom (Dartmouth University) for providing the C. albicans cap1 mutant, and L.D. Chaves (University at Buffalo) for flow cytometric analysis of myeloid cells in the kidneys. We also thank A. Lovett-Racke (Ohio State University) for her advice on in vivo Cblb-knockdown experiments. This work was supported by the US National Institutes of Health (grants R01 AI090901, R01 AI123253, and R21 AI117547; all to J.Z.), the American Heart Association (AHA Great Rivers Associate Grant-in-Aid grant 16GRNT26990004; J.Z.), a start-up fund from the Ohio State University College of Medicine (J.Z.), and the Wellcome Trust (G.D.B.).

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