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Effect of cyclophosphamide on Histoplasma capsulatum infections in mice
Abstract:
Mice were injected intraperitoneally (i.p.) with 300 mg of cyclophosphamide (CY)/kg of body weight, and 24 h later were injected i.p. with varying dosages of yeast-phase cells of Histoplasma capsulatum. At specific time intervals organs were removed, ground, and cultured to determine the number of viable organisms contained in the spleen, liver, and lungs. Injection of mice with CY was found to cause a dramatic increase in the numbers of parasites isolated from these organs when compared with non-drug-treated controls. Mice given 10(7) yeast cells showed the largest increase in colony numbers. A greater than fivefold increase in the numbers of organisms isolated from the spleens of CY and 10(3) yeast cell-treated mice, as compared with non-drug-treated animals, was observed at all time periods. The general trend for infected control animals was a decrease in colony numbers. All mice given CY plus 10(7) yeast cells intravenously (i.v.) died by day 20 postinfection. Mice given CY and 10(7) yeast cells i.p. showed no evidence of fatal Histoplasma infection. Deaths occurring by day 5 in CY-treated animals injected with H. capsulatum yeast cells i.v. or i.p. were considered due to bacterial infection or toxicity, or both. Hepatosplenomegaly was observed in mice treated with CY and 10(7) yeast cells of H. capsulatum. Enlarged lungs were also noted. CY control mouse spleens weighed 30% less than normal spleens. Organs of animals injected with H. capsulatum alone did not vary significantly from those of normal mice. Complete drug-induced suppression of humoral antibody response was achieved for 10 days, as determined by hemagglutination titrations.
Insights
Cyclophosphamide (CY) treatment dramatically increases Histoplasma capsulatum parasite load in mice, impairing immune response. This immunosuppression leads to higher fungal burdens and organ enlargement, highlighting CY
Area of Science:
- Immunology
- Mycology
- Pharmacology
Background:
- Histoplasma capsulatum is an opportunistic fungal pathogen.
- Cyclophosphamide (CY) is an immunosuppressive drug.
- Understanding drug effects on fungal infections is crucial.
Purpose of the Study:
- To investigate the impact of cyclophosphamide (CY) on experimental Histoplasma capsulatum infection in mice.
- To quantify the effect of CY on fungal burden in various organs.
- To assess the influence of CY on survival and host immune response.
Main Methods:
- Mice were treated with cyclophosphamide (CY) and subsequently infected with Histoplasma capsulatum yeast cells.
- Fungal loads in spleen, liver, and lungs were determined by organ culture.
- Survival rates, organ weights, and humoral antibody responses were monitored.
Main Results:
- CY treatment significantly increased Histoplasma capsulatum recovery from spleen, liver, and lungs compared to controls.
- Higher fungal doses (10(7) cells) led to the greatest increase in parasite numbers.
- CY-treated mice showed hepatosplenomegaly and enlarged lungs; CY alone caused spleen atrophy.
- Complete suppression of humoral antibody response was observed for 10 days post-CY treatment.
Conclusions:
- Cyclophosphamide (CY) exacerbates experimental Histoplasma capsulatum infection by increasing fungal burden and causing organ pathology.
- CY-induced immunosuppression significantly impairs the host's ability to control fungal dissemination.
- Further research is needed to understand the clinical implications of immunosuppressive drug use in endemic fungal infections.