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Targeting CBLB as a potential therapeutic approach for disseminated candidiasis

Nature Medicine volume 22, pages 906–914 (2016)Cite this article

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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.

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Figure 1: CBLB inhibits pro-inflammatory cytokine production by macrophages after infection with C. albicans yeast cells or hyphae, and A. fumigatus conidia.
Figure 2: CBLB associates with dectin-1 and dectin-2 in macrophages after infection with C. albicans yeast cells or hyphae.
Figure 3: CBLB targets dectin-1 and dectin-2 for polyubiquitination and subsequent degradation in the lysosome.
Figure 4: Loss of CBLB impairs dectin-1 and dectin-2 internalization and their downregulation at the cell surface.
Figure 5: Introducing a dectin-1 or dectin-2 deficiency, or a double deficiency, into Cblb−/− mice renders Cblb−/− mice susceptible to systemic C. albicans infection.
Figure 6: Systemic in vivo delivery of Cblb-specific siRNA into C57BL/6 mice protects them from lethal disseminated candidiasis.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA

    Yun Xiao, Juan Tang, Hui Guo, Yixia Zhao, Rong Tang, Song Ouyang, Qiuming Zeng, Chad A Rappleye, Murugesan V S Rajaram, Larry S Schlesinger, Belinda T Li & Jian Zhang

  2. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, P.R. China

    Yun Xiao, Juan Tang, Rong Tang & Lijian Tao

  3. Department of Nephrology, Guangzhou Medical University, Guangzhou, P.R. China

    Yun Xiao

  4. Department of Cardiology, Xiangya Hospital, Central South University, Changsha, P.R. China

    Yixia Zhao

  5. Department of Neurology, Xiangya Hospital, Central South University, Changsha, P.R. China

    Song Ouyang & Qiuming Zeng

  6. Department of Neurology, First Hospital of Changsha, University of South China, Changsha, P.R. China

    Song Ouyang

  7. Department of Microbiology, Ohio State University, Columbus, Ohio, USA

    Chad A Rappleye

  8. Aberdeen Fungal Group, MRC Centre for Medical Mycology, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

    Gordon D Brown

  9. School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia

    Wallace Y Langdon

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Contributions

Y.X. performed most of experiments and analyzed the data; J.T., H.G., Y.Z., R.T., S.O., Q.Z., and B.T.L. performed some in vitro and in vivo experiments; C.A.R. helped design the research, analyzed and interpreted the data, and edited the manuscript; M.V.S.R. performed experiments with human macrophages; L.S.S., M.V.S.R., and J.Z. designed human macrophage experiments and edited the manuscript; L.T. helped design kidney experiments and performed data analysis; G.D.B. provided Clec7a−/− mice; W.Y.L. provided CblbC373A knock-in mice and edited the manuscript; and J.Z. conceived and planned the research, analyzed data and wrote the manuscript.

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Correspondence to Jian Zhang.

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Xiao, Y., Tang, J., Guo, H. et al. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat Med 22, 906–914 (2016). https://doi.org/10.1038/nm.4141

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