title: Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.
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.
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, P.R. China.|Department of Nephrology, Guangzhou Medical University, Guangzhou, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Cardiology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Yixia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Nephrology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Tang
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, P.R. China.|Department of Neurology, First Hospital of Changsha, University of South China, Changsha, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Ouyang
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.|Department of Microbiology, Ohio State University, Columbus, Ohio, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Rappleye
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.affiliation: Aberdeen Fungal Group, MRC Centre for Medical Mycology, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Belinda T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D015153:Blotting, Western; D002176:Candida albicans; D058365:Candidiasis, Invasive / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D047468:Immunoprecipitation; D058847:Inflammasomes / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology*; D000072377:Syk Kinase / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology; D000099181:Dectin-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D058847:Inflammasomes; D037181:Lectins, C-Type; D050721:Proto-Oncogene Proteins c-cbl; D017382:Reactive Oxygen Species; D000072377:Syk Kinase; D000099181:Dectin-1; C118387:Cblb protein, mouse; C445340:dectin-2, mouse; C492211:CBLB protein, human; C000606897:Syk protein, mouse