Mary Hummel1, Michael M Abecassis. 1. Department of Surgery, Division of Organ Transplantation, Northwestern University Medical School, Chicago, IL 60611, USA. m-hummel@northwestern.edu
Abstract
BACKGROUND: Reactivation of CMV from latency results in serious morbidity and mortality in immunocompromised transplant recipients. The mechanism by which CMV reactivates from latency has not been well understood. OBJECTIVE: In this review we discuss three models for reactivation from latency and present evidence in favor of the model that reactivation is a multi-step process which is initiated by the allogeneic response to the transplanted organ. Study design (J. Virol. 75 (2001) 4814). Mice latently infected with murine cytomegalovirus (MCMV) were used as donors for allogeneic or syngeneic kidney transplants into immunocompetent recipients. The contralateral donor kidneys were used as controls. Transplanted kidneys were removed at various times after transplant and analyzed for expression of viral genes associated with productive infection and for expression of inflammatory cytokines. Electrophoretic mobility shift assay was performed on nuclear extracts of control and transplanted kidneys to examine activation of AP-1 and NFkappaB. Latently infected mice were also injected with tumor necrosis factor (TNF) to examine the effect of TNF alone on induction of MCMV immediate-early (IE) gene expression. Transgenic major immediate early promoter-lacZ mice carrying a beta-galactosidase reporter gene under the control of the human cytomegalovirus (HCMV) IE promoter/enhancer were used as donors for allogeneic kidney transplants to study the effect of allogeneic transplantation on induction of HCMV IE gene expression. RESULTS: Allogeneic, but not syngeneic transplantation induces MCMV IE-1 expression and expression of inflammatory cytokines, including TNF. Allogeneic transplantation activates transcription factors, including NFkappaB and AP-1. TNF alone can induce MCMV IE-1 gene expression and activation of NFkappaB and AP-1 in some tissues. CONCLUSIONS: We propose that induction of IE-1 gene expression is the first step in reactivation of the virus in an immunocompromised transplant recipient, and that it occurs as a result of the allogeneic response, which induces expression of TNF and subsequent activation of NFkappaB, and ischemia/reperfusion injury, which induces activation of AP-1. We speculate that the natural stimulus for reactivation in an immunocompetent host is an inflammatory immune response to infection and that allogeneic transplantation mimics this process.
BACKGROUND: Reactivation of CMV from latency results in serious morbidity and mortality in immunocompromised transplant recipients. The mechanism by which CMV reactivates from latency has not been well understood. OBJECTIVE: In this review we discuss three models for reactivation from latency and present evidence in favor of the model that reactivation is a multi-step process which is initiated by the allogeneic response to the transplanted organ. Study design (J. Virol. 75 (2001) 4814). Mice latently infected with murine cytomegalovirus (MCMV) were used as donors for allogeneic or syngeneic kidney transplants into immunocompetent recipients. The contralateral donor kidneys were used as controls. Transplanted kidneys were removed at various times after transplant and analyzed for expression of viral genes associated with productive infection and for expression of inflammatory cytokines. Electrophoretic mobility shift assay was performed on nuclear extracts of control and transplanted kidneys to examine activation of AP-1 and NFkappaB. Latently infected mice were also injected with tumor necrosis factor (TNF) to examine the effect of TNF alone on induction of MCMV immediate-early (IE) gene expression. Transgenic major immediate early promoter-lacZ mice carrying a beta-galactosidase reporter gene under the control of the human cytomegalovirus (HCMV) IE promoter/enhancer were used as donors for allogeneic kidney transplants to study the effect of allogeneic transplantation on induction of HCMV IE gene expression. RESULTS: Allogeneic, but not syngeneic transplantation induces MCMV IE-1 expression and expression of inflammatory cytokines, including TNF. Allogeneic transplantation activates transcription factors, including NFkappaB and AP-1. TNF alone can induce MCMV IE-1 gene expression and activation of NFkappaB and AP-1 in some tissues. CONCLUSIONS: We propose that induction of IE-1 gene expression is the first step in reactivation of the virus in an immunocompromised transplant recipient, and that it occurs as a result of the allogeneic response, which induces expression of TNF and subsequent activation of NFkappaB, and ischemia/reperfusion injury, which induces activation of AP-1. We speculate that the natural stimulus for reactivation in an immunocompetent host is an inflammatory immune response to infection and that allogeneic transplantation mimics this process.
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