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Cyclosporin A inhibits Coccidioides immitis in vitro and in vivo
Abstract:
BALB/c mice infected intraperitoneally with Coccidioides immitis were treated with cyclosporin (CyA) subcutaneously. CyA prevented infection when treatment was started at day zero. When treatment was delayed until day 6 after infection, the mice that received either 75 or 25 mg/kg per day survived, but those treated with 7.5 mg/kg per day had the same mortality rate as controls. The higher doses of CyA prevented dissemination of the fungus from the peritoneum to the lung but did not eliminate the peritoneal infection. In vitro, CyA inhibited the growth of the mycelial phase of eight test strains of C. immitis at a concentration of 1.0 microgram/ml. One or two strains of 10 other fungi were tested for susceptibility to CyA; only Aspergillus niger was inhibited, at a concentration of 0.1 microgram/ml. CyA is structurally unrelated to the polyenes and imidazoles and has a very restricted spectrum of antifungal activity. CyA may represent a new class of antifungal agents with a novel mechanism of antifungal activity.
Insights
Cyclosporin (CyA) effectively prevented Coccidioides immitis infection in mice when administered early. Higher doses of CyA reduced fungal dissemination but did not clear the infection.
Area of Science:
- Mycology
- Immunology
- Pharmacology
Background:
- Coccidioides immitis is a fungal pathogen causing significant infections.
- Current antifungal therapies have limitations and resistance is a growing concern.
- Cyclosporin (CyA), an immunosuppressant, was investigated for antifungal properties.
Purpose of the Study:
- To evaluate the in vivo and in vitro efficacy of Cyclosporin (CyA) against Coccidioides immitis.
- To determine the optimal dosage and timing of CyA administration for treating Coccidioides immitis infection.
- To assess the spectrum of antifungal activity of CyA.
Main Methods:
- BALB/c mice were infected intraperitoneally with Coccidioides immitis and treated with varying doses of subcutaneous Cyclosporin (CyA).
- Survival rates, fungal dissemination, and peritoneal infection levels were monitored.
- In vitro growth inhibition assays were performed on Coccidioides immitis and other fungal species using CyA.
Main Results:
- Early administration of CyA prevented infection in mice.
- Higher doses (75 and 25 mg/kg/day) of CyA administered post-infection improved survival and prevented fungal dissemination to the lungs.
- CyA inhibited the mycelial growth of Coccidioides immitis in vitro at 1.0 microgram/ml and Aspergillus niger at 0.1 microgram/ml, indicating a narrow antifungal spectrum.
Conclusions:
- Cyclosporin (CyA) demonstrates preventative and therapeutic potential against Coccidioides immitis infection in a murine model.
- Higher doses of CyA can mitigate infection severity and dissemination, though not eradicate the primary infection.
- CyA exhibits a restricted antifungal spectrum, suggesting a novel mechanism of action distinct from established antifungal drug classes.