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Published on: January 9, 2013
Systemic infection by Candida albicans requires FASN-α subunit induced cell wall remodeling to perturb immune
Yajing Zhao1,2, Zhishan Zhou1,2, Guiyue Cai1,2
1Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Abstract:
Invasive fungal infections are a leading cause of mortality and morbidity in patients with severely impaired host defenses, while treatment options remain limited. Fatty acid synthase (FASN), the key enzyme regulating de novo biosynthesis of fatty acids, is crucial for the lethal infection of fungi; however, its pathogenic mechanism is still far from clear. Here, we identified the α subunit of FASN as a potential immunotherapeutic target against systemic Candida albicans infection. The avirulence of the encoded gene (FAS2) -deleted mutant in a mouse model of systemic candidiasis is not due to its fitness defects, because sufficient exogenous fatty acids in serum can overcome FASN inhibition. However, the FAS2-deleted mutant displays increased circulating innate immune responses and enhances activated neutrophil fungicidal activity through the unmasking of immunogenic cell wall epitopes via the Rho-1 dependent Mkc1-MAPK signaling pathway, which facilitates fungal clearance, reduces renal tissue damage and inflammatory cell infiltration, ultimately lowers fungal pathogenicity. Priming with the FAS2-deleted mutant provided significant protection against subsequent lethal infection with wild-type C. albicans in mice as early as one week, and it was well-tolerated with limited toxicity. Our findings indicate that the FASN-α subunit plays key roles in the regulation of neutrophil-associated antifungal immunity and could be a potential target for immunotherapeutic intervention.
Insights
Fatty acid synthase (FASN) alpha subunit is a novel target for invasive fungal infections. Disrupting FASN in Candida albicans enhances immune responses and provides protection against lethal infections.
Area of Science:
- Mycology
- Immunology
- Biochemistry
Background:
- Invasive fungal infections cause significant mortality, especially in immunocompromised patients.
- Limited treatment options necessitate novel therapeutic strategies.
- Fatty acid synthase (FASN) is vital for fungal survival, but its role in pathogenesis is unclear.
Purpose of the Study:
- To investigate the FASN alpha subunit as a potential immunotherapeutic target against Candida albicans.
- To elucidate the pathogenic mechanisms of FASN in fungal infections.
Main Methods:
- Deletion of the FASN alpha subunit gene (FAS2) in Candida albicans.
- Evaluation of the FAS2-deleted mutant's virulence in a mouse model of systemic candidiasis.
- Assessment of innate immune responses, neutrophil fungicidal activity, and signaling pathways (Rho-1, Mkc1-MAPK).
Main Results:
- FAS2 deletion attenuated fungal pathogenicity without fitness defects, as exogenous fatty acids compensated for FASN inhibition.
- The FAS2-deleted mutant induced heightened innate immune responses and enhanced neutrophil fungicidal activity.
- This enhancement was mediated by unmasked cell wall epitopes via the Rho-1/Mkc1-MAPK pathway, leading to reduced fungal burden and tissue damage.
- Priming with the FAS2-deleted mutant conferred significant protection against subsequent wild-type C. albicans infection in mice with minimal toxicity.
Conclusions:
- The FASN alpha subunit is critical for regulating neutrophil-mediated antifungal immunity.
- Targeting the FASN alpha subunit represents a promising strategy for immunotherapeutic intervention against invasive fungal infections.
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