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Acute murine cytomegalovirus infection: a model for determining antiviral activity against CMV induced hepatitis
G Bolger1, N Lapeyre, M Rhéaume
1Department of Biological Sciences, Boehringer Ingelheim (Canada) Limited, Laval, Quebec, Canada.
Abstract:
Acute intraperitoneal infection of weanling BALB/c mice with murine cytomegalovirus (MCMV) resulted in an inoculum titer-dependent weight loss, mortality and elevation of plasma transaminases (ALT: alanine transaminase and AST: aspartate transaminase). Three days post infection (p.i.) with 10(4.85) plaque forming units (pfu) there was 90% mortality with a mean death day p.i. of 4.1 +/- 0.2. Plasma levels of ALT and AST were elevated 24- and 15-fold, respectively. Organ titers of virus (log10 pfu/g tissue) were 6.16 in the liver, 6.05 in the spleen, 4.0-4.7 in the lung, heart, kidney and intestine and undetectable in the muscle and brain. Organ concentrations (units/g wet-weight) of ALT were highest in the liver, whilst for AST the highest levels were found in the heart. The concentrations of ALT but not AST were reduced (35-55%) in the infected liver; the concentrations of ALT and AST were not changed in other infected organs. There were excellent correlations (r > 0.95) between viral titers in the liver, increases of plasma ALT and depletion of liver ALT. HPMPC and ganciclovir administered either p.o. or s.c. reduced mortality, increases in plasma transaminases and viral burdens in the liver and prevented depletion of liver ALT. HPMPC was approximately 10-fold more potent than ganciclovir. These results strongly suggest that intraperitoneal infection of the BALB/c mouse with MCMV represents an animal model of CMV hepatitis that can be monitored by measuring plasma ALT.
Insights
Murine cytomegalovirus (MCMV) infection in mice causes liver damage, indicated by elevated alanine transaminase (ALT) and aspartate transaminase (AST) in plasma. Antiviral drugs like HPMPC and ganciclovir effectively reduced mortality and liver injury.
Area of Science:
- Virology
- Hepatology
- Immunology
Background:
- Murine cytomegalovirus (MCMV) is a significant pathogen in mice.
- Cytomegalovirus (CMV) infections can cause hepatitis in humans.
- Establishing reliable animal models is crucial for studying CMV pathogenesis and treatment.
Purpose of the Study:
- To characterize a murine model of cytomegalovirus hepatitis.
- To evaluate the efficacy of antiviral agents in treating MCMV-induced liver disease.
- To establish plasma ALT as a biomarker for MCMV hepatitis.
Main Methods:
- BALB/c mice were infected intraperitoneally with MCMV.
- Mortality, weight loss, and plasma transaminase levels (ALT, AST) were monitored.
- Viral titers in various organs were quantified.
- Organ concentrations of ALT and AST were measured.
- Mice were treated with HPMPC and ganciclovir.
Main Results:
- MCMV infection led to dose-dependent weight loss, mortality, and elevated plasma ALT and AST.
- High viral loads were found in the liver and spleen.
- Liver ALT concentrations decreased significantly, correlating with viral load and plasma ALT.
- HPMPC and ganciclovir reduced mortality, viral burden, and plasma transaminase elevations.
- HPMPC demonstrated higher potency than ganciclovir.
Conclusions:
- Intraperitoneal MCMV infection in BALB/c mice serves as a valuable model for CMV hepatitis.
- Plasma ALT levels are a reliable indicator of MCMV-induced liver injury.
- Antiviral therapy with HPMPC and ganciclovir is effective in mitigating MCMV hepatitis and mortality.