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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    Xiao, Y., Tang, J., Guo, H., Zhao, Y., Tang, R., Ouyang, S., Zeng, Q., Rappleye, C. A., Rajaram, M. V. S., Schlesinger, L. S., Tao, L., Brown, G. D., Langdon, W. Y., Li, B. T., & 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