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Published on: December 8, 2011
Evaluation of a murine model of hepatic candidiasis
G T Cole1, K T Lynn, K R Seshan
1Department of Botany, University of Texas, Austin 78713-7640.
Abstract:
A murine model of focal hepatic candidiasis which we suggest simulates certain conditions of this clinical variant of systemic candidiasis in leukemic patients is described. We have shown that outbred mice inoculated with Candida albicans by the oral-intragastric route as infants (6 days old) and then immunocompromised by cyclophosphamide and cortisone acetate treatment 2 weeks later demonstrate systemic spread of the opportunistic pathogen to the liver, lungs, spleen, and kidneys. Treatment with the immunosuppressive drugs cyclophosphamide and cortisone acetate resulted in alteration of the normal integrity of the mucosal epithelium of the gut as well as in granulocytopenia. Approximately 55% of the animals with C. albicans infections in the liver demonstrated hepatic abscesses. After these same infected, immunocompromised animals were treated with suboptimal dosages of antifungal agents (cilofungin or amphotericin B), either by intraperitoneal or subcutaneous (s.c.) routes, persistent hepatic abscesses were fewer in number and delimited by a distinct outer layer of host tissue but still contained large numbers of the viable pathogen. Blood cell counts indicated that these antifungal drug-treated animals had reestablished approximately the same number of leukocytes per microliter of blood as estimated prior to the immunocompromising drug treatment. Similar conditions in leukemic patients who were in remission and who were undergoing antifungal drug therapy for systemic candidiasis have been reported. Clearance of hepatic infections in mice was accomplished by using appropriate concentrations of amphotericin B administered by daily intraperitoneal or s.c. injection for 5 to 7 days or cilofungin by continuous s.c. infusion for 7 days. However, systemic antifungal therapy did not significantly reduce numbers of C. albicans cells in the stomach and esophagus. Persistent foci of gastrointestinal colonization by C. albicans, especially in the region of the cardial-atrium fold of the stomach of these mice, are reservoirs of the opportunistic pathogen from which reinfection may occur, leading to relapse of systemic candidiasis.
Insights
This study developed a murine model for hepatic candidiasis in immunocompromised mice, showing that while antifungal drugs reduced liver abscesses, gastrointestinal Candida albicans colonization persisted, risking relapse.
Area of Science:
- Mycology
- Immunology
- Infectious Diseases
Background:
- Systemic candidiasis is a serious opportunistic infection, particularly in immunocompromised individuals like leukemic patients.
- Focal hepatic candidiasis presents unique challenges in treatment and management.
- Understanding pathogen reservoirs is crucial for preventing relapse.
Purpose of the Study:
- To establish and characterize a murine model of focal hepatic candidiasis.
- To evaluate the efficacy of antifungal agents in treating systemic candidiasis in an immunocompromised setting.
- To identify potential reservoirs for Candida albicans recurrence.
Main Methods:
- Developed a murine model by orally inoculating infant mice with Candida albicans and inducing immunosuppression with cyclophosphamide and cortisone acetate.
- Administered suboptimal dosages of antifungal agents (cilofungin or amphotericin B) to infected, immunocompromised mice.
- Assessed hepatic abscesses, pathogen load in various organs, and blood cell counts.
Main Results:
- Immunosuppression led to systemic spread of Candida albicans to the liver, lungs, spleen, and kidneys, with hepatic abscesses forming in 55% of infected animals.
- Suboptimal antifungal treatment reduced the number of hepatic abscesses but did not eliminate viable Candida albicans within them.
- Effective clearance of hepatic infections was achieved with appropriate amphotericin B or cilofungin treatment, but gastrointestinal colonization persisted.
Conclusions:
- The murine model effectively simulates focal hepatic candidiasis seen in immunocompromised patients.
- Persistent gastrointestinal Candida albicans colonization, particularly in the stomach, serves as a reservoir for potential relapse of systemic infection.
- Targeting gastrointestinal reservoirs may be necessary for complete eradication and prevention of relapse in systemic candidiasis.
