Effects of immunosuppression with cyclophosphamide on acute murine cytomegalovirus infection and virus augmented natural killer cell activity

Abstract

The effects of cyclophosphamide (CY) treatment on acute murine cytomegalovirus (MCMV) infection were studied to explore the potential usefulness of MCMV as a means of detecting immune dysfunction and to identify host defense mechanisms important for protection against MCMV. Conditions found optimal for enhancing MCMV infection with CY included infecting adult mice with 2 x 105 PFU or more of virus and administering 80 mg or more of CY per kg 1 to 3 days later. In addition to enhanced mortality, virus titers in lung, liver, and spleen were elevated in CY-treated mice, and wet weights of liver, spleen, and thymus were depressed when compared with those of infected but untreated mice. Treatment with CY before MCMV challenge was not as efficient a means of enhancing mortality as treatment after virus challenge. The effect that the time of CY administration relative to infection had on mortality correlated with the effect of such timing on natural killer cell activity. Animals treated before infection exhibited depressed natural killer cell activity initially. However, they rapidly recovered this response, and by 5 days postinfection they had the same level of virus-augmented activity seen in untreated mice. In contrast, animals treated after infection did not recover natural killer cell activity and were more likely to die. A similar correlation was not obtained when the effects of CY on lymphocyte responses to B and T cell mitogens were examined, nor were there striking differences in pathology between the treatment groups. The data suggest an important role for natural killer cells in host defense against MCMV. Also, increased susceptibility to MCMV may provide a useful indicator of deficits in the natural killer cell response.