Inhibition of CBLB protects from lethal Candida albicans sepsis

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.

Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs?

“…Of note, all antifungal drugs target fungal growth in the host. However, there is increasing and compelling evidence that modulating the amplitude and magnitude of the host inflammatory immune response can be beneficial for the outcome of invasive fungal diseases [60–62]. Thus, chromatin-mediated adaptive changes during fungal pathogen host interplay opens new windows of opportunities and may hold great promises for future antifungal drug discovery.…”

Fungal dysbiosis: immunity and interactions at mucosal barriers

“…A recent study demonstrated that inhibition of JNK1 promotes expression of CD23 (a recently discovered CLR), production for nitric oxide and a potent antifungal effect both in vitro and in vivo 117 . E3 ubiquitin ligase CBLB that ubiquitinates SYK, was shown to regulate antifungal immune responses downstream of dectin-1 and dectin-2 (Figure 3) 118,119 . Genetic deletion or peptide-based inhibition of CBLB promoted strong antifungal response, enhanced fungal killing and protected mice during systemic and cutaneous C. albicans infections 118 .…”

Immunity against fungi

“…As these CLRs lack a signaling domain, heterodimeric complexes signal via the ITAM-coupled adaptor FcRγ (9). Following fungal recognition, the E3 ubiquitin ligase CBLB ubiquitinates dectin-1, dectin-2, and SYK, targeting them for degradation (50)(51)(52). In systemic candidiasis, Cblb -/-mice exhibit reduced renal fungal burden and improved survival due to decreased inflammation-driven tissue damage (50)(51)(52).…”

“…Following fungal recognition, the E3 ubiquitin ligase CBLB ubiquitinates dectin-1, dectin-2, and SYK, targeting them for degradation (50)(51)(52). In systemic candidiasis, Cblb -/-mice exhibit reduced renal fungal burden and improved survival due to decreased inflammation-driven tissue damage (50)(51)(52). In contrast, TRIM62-mediated CARD9 ubiquitination is essential for BCL10 interactions, NF-κB activation, and defense against candidiasis (53).…”