A clinically relevant murine model unmasks a "two-hit" mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant.
Zheng ZhangLonghui QiuShixian YanJiao-Jing WangPaul M ThomasManoj KandpalLihui ZhaoAndre IovaneXue-Feng LiuEdward B ThorpQing ChenMary HummelYashpal S KanwarMichael M I AbecassisPublished in: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2019)
Reactivation of latent cytomegalovirus remains an important complication after transplant. Although immunosuppression (IS) has been implicated as a primary cause, we have previously shown that the implantation response of a kidney allograft can lead to early transcriptional activation of latent murine cytomegalovirus (MCMV) genes in an immune-competent host and to MCMV reactivation and dissemination to other organs in a genetically immune-deficient recipient. We now describe a model that allows us to separately analyze the impact of the implantation effect vs that of a clinically relevant IS regimen. Treatment with IS of latently infected mice alone does not induce viral reactivation, but transplant of latently infected allogeneic kidneys combined with IS facilitates MCMV reactivation in the graft and dissemination to other organs. The IS regimen effectively dampens allo-immune inflammatory pathways and depletes recipient anti-MCMV but does not affect ischemia-reperfusion injury pathways. MCMV reactivation similar to that seen in allogeneic transplants combined with also occurs after syngeneic transplants. Thus, our data strongly suggest that while ischemia-reperfusion injury of the implanted graft is sufficient and necessary to initiate transcriptional reactivation of latent MCMV ("first hit"), IS is permissive to the first hit and facilitates dissemination to other organs ("second hit").
Keyphrases
- ischemia reperfusion injury
- stem cell transplantation
- oxidative stress
- epstein barr virus
- gene expression
- bone marrow
- sars cov
- transcription factor
- type diabetes
- genome wide
- big data
- adipose tissue
- electronic health record
- metabolic syndrome
- dna methylation
- skeletal muscle
- artificial intelligence
- kidney transplantation