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Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism
S C Lee1, D W Dickson, C F Brosnan
1Department of Pathology Neuropathology, Albert Einstein College of Medicine, Bronx, New York 10461.
Abstract:
Cryptococcus neoformans is an opportunistic fungus that causes life-threatening meningoencephalitis in 5-10% of patients with acquired immune deficiency syndrome. Cryptococcal meningoencephalitis is characterized by a lymphohistiocytic infiltrate, accumulation of encapsulated forms of C. neoformans, and varying degrees of glial reaction. Little is known about the contribution of endogenous central nervous system cells to the pathogenesis of cryptococcal infections. In this study, we investigated the role of astrocytes as potential effector cells against C. neoformans. Primary cultures of human fetal astrocytes, activated with interleukin 1 beta plus interferon gamma inhibited the growth of C. neoformans. The inhibition of C. neoformans growth was paralleled by production of nitrite, and reversed by the inhibitors of nitric oxide (NO.) synthase, NG-methyl-mono-arginine and NG-nitro-arginine methyl ester. The results suggest a novel function for human astrocytes in host defence and provide a precedent for the use of NO. as an antimicrobial effector molecule by human cells.
Insights
Human astrocytes, activated by specific cytokines, inhibit Cryptococcus neoformans growth by producing nitric oxide (NO). This finding reveals a novel role for astrocytes in fighting fungal infections in the central nervous system.
Area of Science:
- Neuroimmunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcus neoformans causes life-threatening meningoencephalitis in immunocompromised individuals.
- The role of endogenous central nervous system cells in cryptococcal infection pathogenesis is poorly understood.
Purpose of the Study:
- To investigate the potential role of astrocytes as effector cells against Cryptococcus neoformans.
- To explore the mechanisms by which astrocytes might combat fungal infections in the brain.
Main Methods:
- Primary cultures of human fetal astrocytes were utilized.
- Astrocytes were activated using interleukin-1 beta and interferon-gamma.
- Nitrite production and the effect of nitric oxide synthase inhibitors (NG-methyl-mono-arginine, NG-nitro-arginine methyl ester) were measured.
Main Results:
- Activated human astrocytes demonstrated inhibition of Cryptococcus neoformans growth.
- This growth inhibition was associated with increased nitrite production.
- Inhibitors of nitric oxide synthase reversed the antifungal effect, implicating nitric oxide.
Conclusions:
- Human astrocytes possess a novel defense mechanism against Cryptococcus neoformans.
- Nitric oxide is identified as a key antimicrobial effector molecule produced by astrocytes.
- These findings highlight astrocytes' contribution to host defense in central nervous system fungal infections.