A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

Zheng Jenny Zhang, Longhui Qiu, Shixian Yan, Jiao Jing Wang, Paul Martin Thomas, Manoj Kandpal, Lihui Zhao, Andre Iovane, Xuefeng Liu, Edward Benjamin Thorp, Qing Ching Chen, Mary Anne Hummel, Yashpal S Kanwar, Michael Messod Abecassis*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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”).

Original languageEnglish (US)
Pages (from-to)2421-2433
Number of pages13
JournalAmerican Journal of Transplantation
Volume19
Issue number9
DOIs
StatePublished - Jan 1 2019

Fingerprint

Muromegalovirus
Cytomegalovirus
Immunosuppression
Transplants
Kidney
Reperfusion Injury
Transcriptional Activation
Allografts
Wounds and Injuries
Genes

Keywords

  • animal models: murine
  • basic (laboratory) research/science
  • immunosuppression/immune modulation
  • immunosuppressive regimens
  • infection and infectious agents - viral: Cytomegalovirus (CMV)
  • infectious disease
  • ischemia reperfusion injury (IRI)
  • kidney transplantation/nephrology
  • signaling/signaling pathways
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

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title = "A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant",
abstract = "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”).",
keywords = "animal models: murine, basic (laboratory) research/science, immunosuppression/immune modulation, immunosuppressive regimens, infection and infectious agents - viral: Cytomegalovirus (CMV), infectious disease, ischemia reperfusion injury (IRI), kidney transplantation/nephrology, signaling/signaling pathways, translational research/science",
author = "Zhang, {Zheng Jenny} and Longhui Qiu and Shixian Yan and Wang, {Jiao Jing} and Thomas, {Paul Martin} and Manoj Kandpal and Lihui Zhao and Andre Iovane and Xuefeng Liu and Thorp, {Edward Benjamin} and Chen, {Qing Ching} and Hummel, {Mary Anne} and Kanwar, {Yashpal S} and Abecassis, {Michael Messod}",
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TY - JOUR

T1 - A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant

AU - Zhang, Zheng Jenny

AU - Qiu, Longhui

AU - Yan, Shixian

AU - Wang, Jiao Jing

AU - Thomas, Paul Martin

AU - Kandpal, Manoj

AU - Zhao, Lihui

AU - Iovane, Andre

AU - Liu, Xuefeng

AU - Thorp, Edward Benjamin

AU - Chen, Qing Ching

AU - Hummel, Mary Anne

AU - Kanwar, Yashpal S

AU - Abecassis, Michael Messod

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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”).

AB - 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”).

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KW - basic (laboratory) research/science

KW - immunosuppression/immune modulation

KW - immunosuppressive regimens

KW - infection and infectious agents - viral: Cytomegalovirus (CMV)

KW - infectious disease

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KW - kidney transplantation/nephrology

KW - signaling/signaling pathways

KW - translational research/science

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JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

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