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Defective co-stimulation and impaired Th1 development in tumor necrosis factor/lymphotoxin-alpha double-deficient
A Mencacci1, E Cenci, G Del Sero
1Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
Abstract:
To define the immunological functions of tumor necrosis factor (TNF) in Candida albicans infection, TNF/lymphotoxin (LT)-alpha double-deficient mice were assessed for susceptibility to systemic or gastrointestinal infection and parameters of innate and adaptive Th immunity. When compared to wild-type mice, TNF/LT-alpha-deficient mice were more susceptible to either type of infection caused by virulent or low-virulence C. albicans cells. Susceptibility to infection correlated with impaired development of protective Th1 responses, in spite of the production of bioactive IL-12. The occurrence of predominant Th2 responses was associated with both impaired antifungal effector functions of neutrophils and a defective expression of co-stimulatory molecules on macrophages. All functions were improved upon administration of recombinant TNF-alpha, also resulting in increased resistance to infection. These findings indicate that the protective effect of TNF-alpha in candidiasis relies on the induction of antifungal Th1 responses, possibly occurring through stimulation of antifungal effector functions and co-stimulatory activities of phagocytic cells.
Insights
Tumor necrosis factor-alpha (TNF) is crucial for controlling Candida albicans infections by promoting Th1 immune responses. Supplementing TNF-alpha enhances antifungal immunity and resistance.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) play roles in immune responses.
- Candida albicans is an opportunistic fungal pathogen causing various infections.
Purpose of the Study:
- To elucidate the immunological functions of TNF in Candida albicans infection.
- To assess the role of TNF/LT-alpha in innate and adaptive immunity against C. albicans.
Main Methods:
- Utilized TNF/LT-alpha double-deficient mice and wild-type controls.
- Inoculated mice with virulent and low-virulence C. albicans strains for systemic and gastrointestinal infections.
- Administered recombinant TNF-alpha to assess its therapeutic potential.
Main Results:
- TNF/LT-alpha-deficient mice exhibited increased susceptibility to C. albicans infections.
- Impaired Th1 responses and predominant Th2 responses were observed in deficient mice.
- Neutrophil antifungal functions and macrophage co-stimulatory molecule expression were defective.
- Recombinant TNF-alpha administration improved immune functions and increased resistance.
Conclusions:
- TNF-alpha is essential for inducing protective Th1 responses against candidiasis.
- TNF-alpha enhances antifungal effector functions and co-stimulatory activities of phagocytes.
- TNF-alpha administration represents a potential therapeutic strategy for C. albicans infections.