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Effects of FK-506 on the course of murine salmonellosis
T Nichterlein1, M Kretschmar, G Geginat
1Institute of Medical Microbiology and Hygiene, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
Abstract:
Bacterial infections are a major threat to immunocompromised patients. Therefore, the effect of immunosuppression with cyclosporin A and FK-506 on the course of murine salmonellosis was tested. Treatment of mice with both substances reduced the amount of circulating CD4+ T-cells and CD8+ T-cells in uninfected and infected mice. The substances effectively suppressed the proliferation of spleen cells of treated mice upon activation with concanavalin A (ConA) and upon activation by mouse peritoneal macrophages infected with live salmonellae, but left the response to lipopolysaccharide (LPS) unaltered. In particular, treatment of mice with nontoxic doses led to an increase in Salmonella typhimurium counts in the organs of primarily infected mice from day 14 onward, but not in the early phase of infection. In mice treated during secondary infection with S. typhimurium the bacterial counts in the organs were increased from day 3 of infection onward. We conclude that both substances aggravate murine salmonellosis, most likely by inhibition of T-cell function. Patients receiving FK-506 might also be, therefore, at risk of salmonella infection.
Insights
Immunosuppressants cyclosporin A and FK-506 worsen Salmonella infections in mice by inhibiting T-cell function. This increases bacterial load, posing risks for patients on FK-506, especially those with compromised immunity.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Immunocompromised patients are highly susceptible to bacterial infections.
- Cyclosporin A and FK-506 are immunosuppressive drugs used in transplantation and autoimmune diseases.
- Salmonellosis is a significant concern in vulnerable populations.
Purpose of the Study:
- To investigate the impact of cyclosporin A and FK-506 on the course of murine salmonellosis.
- To determine the effects of these immunosuppressants on T-cell populations and function.
- To assess the implications for patients receiving these medications.
Main Methods:
- Mice were treated with cyclosporin A or FK-506 during primary and secondary Salmonella typhimurium infections.
- Circulating CD4+ and CD8+ T-cell counts were measured.
- Spleen cell proliferation was assessed in response to concanavalin A (ConA), lipopolysaccharide (LPS), and infected macrophages.
- Bacterial loads in organs were quantified.
Main Results:
- Both cyclosporin A and FK-506 reduced circulating CD4+ and CD8+ T-cells.
- Spleen cell proliferation was suppressed upon ConA and infected macrophage activation, but not LPS activation.
- Organ bacterial counts of Salmonella typhimurium were significantly increased in treated mice, particularly during secondary infection.
- These effects were observed at nontoxic doses of the immunosuppressants.
Conclusions:
- Cyclosporin A and FK-506 aggravate murine salmonellosis, likely through T-cell function inhibition.
- FK-506 treatment may increase the risk of Salmonella infection in patients.
- Understanding these drug effects is crucial for managing infections in immunosuppressed individuals.