Cbl-b Inhibition as a Therapeutic Approach to Disseminated Candidiasis
Disseminated C. albicans infection in patients who have a weakened immune system is life threatening and causes 40% of bloodstream infections (candidemia) in hospitals. Despite the availability of several antifungal drugs, invasive candidiasis still has a high mortality rate ranging from 19-40% (Morgan, et al. 2005; Kullberg et al. 2015). While risk factors can include health-care or host-associated factors, high morbidity and mortality rates associated with disseminated candidiasis are mainly attributed to immunosuppressive diseases, invasive interventions, drug resistance, and the lack of early and accurate diagnostic tools. These problems highlight the need to further understand host-pathogen interactions and the mechanisms of immune resistance to fungal spread, and to develop alternative immune-based strategies to combat candidemia.
Researchers at The Ohio State University, led by Dr. Jian Zhang, have discovered a method to prevent fungal infection by regulating CBL-b, an E3 ubiquitin ligase that contains multiple functional domains. They found that CBL-b negatively regulates Dectin-1 and Dectin-2, which help guide the immune system responses against fungal infections. In vivo studies in mice showed that when a therapeutically effective amount of CBL-b inhibitor was delivered using siRNA or other nucleic acid knock-down methods, mice were protected from an otherwise lethal dose of C. albicans. Further studies indicate that knocking down CBL-b in human cells enhances IL-6 and TNF-alpha production, indicating homeostatic control of immune responses against C.albicans infection. In vivo silencing of CBL-b through siRNA genetic modification is a novel approach to preventing candidemia infection or treating patients with disseminated candidiasis.
- Treatment of infections from Candida spp.
- Treats fungal infections in subjects undergoing immunotherapy