Inhibition of CBLB protects from lethal Candida albicans sepsis

Nat Med. 2016 Aug;22(8):915-23. doi: 10.1038/nm.4134. Epub 2016 Jul 18.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Blotting, Western
  • Candida albicans
  • Candidiasis, Invasive / immunology*
  • Caspase 8
  • Cytokines / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Immunoprecipitation
  • Kidney
  • Lectins, C-Type / drug effects
  • Lectins, C-Type / metabolism*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Peptides / pharmacology*
  • Phagocytosis / drug effects
  • Phagocytosis / genetics
  • Phagocytosis / immunology*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-cbl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / immunology*
  • Reactive Oxygen Species / immunology*
  • Sepsis / immunology*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cblb protein, mouse
  • Cytokines
  • Lectins, C-Type
  • Peptides
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-cbl
  • Casp8 protein, mouse
  • Caspase 8