Targeting CBLB as a potential therapeutic approach for disseminated candidiasis
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Published on: September 16, 2022
Yun Xiao1,2,3, Juan Tang1,2, Hui Guo1
1Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA.
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.
Insights
The E3 ubiquitin ligase CBLB inhibits key immune responses against Candida albicans. CBLB inactivation protects mice from lethal candidiasis, identifying CBLB as a potential therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Microbiology
Background:
- Disseminated candidiasis is a major hospital-acquired infection with high mortality.
- The molecular mechanisms of host defense against Candida albicans are not fully understood.
- Current treatment options for disseminated candidiasis are limited.
Purpose of the Study:
- To investigate the role of the E3 ubiquitin ligase CBLB in host defense against disseminated candidiasis.
- To elucidate the molecular mechanisms by which CBLB regulates innate immune responses to Candida albicans.
- To evaluate CBLB as a potential therapeutic target for disseminated candidiasis.
Main Methods:
- Investigated the polyubiquitination of dectin-1, dectin-2, and SYK by CBLB.
- Utilized Cblb-deficient mice to assess protection against lethal C. albicans infection.
- Examined the impact of dectin-1 and dectin-2 deficiency in Cblb(-/-) mice.
- Performed in vivo gene silencing of Cblb.
Main Results:
- CBLB directs polyubiquitination of dectin-1, dectin-2, and SYK, inhibiting their immune functions.
- CBLB deficiency or inactivation confers protection against lethal systemic C. albicans infection in mice.
- Deficiency of dectin-1, dectin-2, or both abrogates CBLB-mediated protection.
- In vivo silencing of Cblb protects mice from lethal candidiasis.
Conclusions:
- CBLB plays a critical role in the homeostatic control of innate immune responses mediated by dectin-1 and dectin-2.
- CBLB represents a promising therapeutic target for the treatment of disseminated candidiasis.
