Mechanisms of MCMV reactivation in immunodeficient transplant recipients

Project: Research project

Project Details

Description

Reactivation of latent human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in transplant recipients, despite the use of antiviral drugs. Therefore, new approaches are required to reduce the complications from this pathogen. Due to the species specificity of HCMV, we have developed a novel transplant model using the highly related murine CMV (MCMV) as a model to study CMV latency and reactivation in the context of organ transplantation. In this model, MCMV latently infected kidneys are transplanted into immunocompromised NOD.Cg-PrkdcscidIL2rgtm1Wjl/Szj (NSG) mice, which are deficient in T, B, and NK cells. Transplantation of latently infected kidneys into NSG recipients results in reactivation of latent virus in the donor kidney, which disseminates systemically. Reactivation of HCMV is associated with various inflammatory insults. Our preliminary data shows that IL-6, soluble CD40L, IL-18, and LIF are elevated in the plasma of recipient mice with timing consistent with a causal role in reactivation. IL-6 induces reactivation of HCMV in hematopoietic cell models. The central hypothesis of this proposal is that the inflammatory response elicited by the transplanted kidney results in the release of mediators in the recipient mice. The resulting signaling cascade stimulates epigenetic reprogramming of latent viral genomes, transcriptional reactivation of viral immediate early (IE) gene expression, and in immunocompromised recipients, re-entry of latent virus into the lytic replication program. To test this hypothesis, in Aim 1 we will
investigate the requirement for candidate factors identified in our preliminary studies, and their downstream signaling intermediates, in inducing reactivation in the NSG model. Our previous studies and those of others show that lytic viral gene expression is repressed in CMV latency due to heterochromatinization of viral genomes. In addition, we have shown that transplant-induced reactivation of MCMV immediate early gene
expression is associated with epigenetic reprogramming. Previous studies by our collaborator, Dr. Thomas Kristie, have identified epigenetic inhibitors that suppress reactivation of latent herpes simplex virus. In Aim 2 we will investigate these promising therapeutic interventions for their ability to prevent reactivation of latent MCMV in the NSG model. Finally, in Aim 3 we will investigate new in vitro models for MCMV latency and differentiation-induced reactivation in murine hematopoietic progenitor cells. This complementary in vitro model would be exceptionally useful for defining molecular mechanisms in the absence of the complexity of the organism. Upon completion, our studies will have identified signaling pathways that lead to epigenetic reprogramming of viral chromatin to reactivate latent MCMV in response to transplantation and potential therapeutic targets.
StatusFinished
Effective start/end date7/1/146/30/19

Funding

  • National Institute of Allergy and Infectious Diseases (5R01AI112911-03)

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