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Mechanisms of MCMV reactivation in immunodeficient transplant recipients

免疫缺陷移植受者中 MCMV 再激活的机制

基本信息

批准号：
9295934
负责人：
Michael M Abecassis
金额：
$ 44.3万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295934
关键词：
Acute Allogenic Alpha Cell Antiviral Agents B-Lymphocytes Binding Biological Models Bone Marrow Bone Marrow Cells Cell Differentiation process Cell model Cells Chromatin Collaborations Cytomegalovirus Data Dendritic Cells Development Disease Early Promoters Epigenetic Process Gene Expression Genetic Transcription Genome Goals Hematopoietic Hematopoietic stem cells Herpesviridae Histones Human Immediate-Early Genes Immunocompromised Host In Vitro Infection Inflammation Mediators Inflammatory Inflammatory Response Interleukin-18 Interleukin-6 Kidney Kidney Transplantation LIF gene Latent Virus Lead Lysine Lytic Mediating Mediator of activation protein Methylation Modeling Molecular Morbidity - disease rate Murid herpesvirus 1 Mus Natural Killer Cells Organ Transplantation Organism Phenotype Plasma Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Simplexvirus Site Species Specificity Study models System T-Lymphocyte TNFSF5 gene Testing Therapeutic Intervention Transcriptional Activation Transplant Recipients Transplantation United States National Institutes of Health Viral Viral Genes Viral Genome Virus Virus Latency demethylation extracellular histone demethylase histone methylation histone methyltransferase in vitro Model in vivo inhibitor/antagonist latent infection lytic replication monocyte mortality neutralizing antibody novel novel strategies novel therapeutics pathogen prevent programs public health relevance reactivation from latency response therapeutic target transcription factor viral DNA

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请方提供）：尽管使用了抗病毒药物，但潜伏性人巨细胞病毒（HCMV）的再活化仍然是移植受者发病和死亡的重要原因。因此，需要新的方法来减少这种病原体的并发症。由于HCMV的种属特异性，我们已经开发了一种新的移植模型，使用高度相关的小鼠CMV（MCMV）作为模型来研究CMV潜伏期和再激活的背景下，器官移植。在该模型中，将MCMV潜伏感染的肾脏移植到免疫受损的NOD. Cg-PrkdcscidIL 2 rgtm 1 Wjl/Szj（NSG）小鼠中，其缺乏T、B和NK细胞。将潜伏感染的肾脏移植到NSG受体中会导致供体肾脏中潜伏病毒的重新激活，从而全身传播。HCMV的再活化与各种炎症损伤有关。我们的初步数据表明，IL-6，可溶性CD 40 L，IL-18，和LIF在受体小鼠的血浆中升高的时间与再激活的因果作用一致。IL-6在造血细胞模型中诱导HCMV的再活化。该建议的中心假设是，移植肾引起的炎症反应导致受体小鼠释放介质。所产生的信号级联刺激潜伏病毒基因组的表观遗传重编程、病毒立即早期（IE）基因表达的转录再激活，以及在免疫受损的接受者中，潜伏病毒重新进入裂解复制程序。为了验证这一假设，在目标1中，我们将研究在我们的初步研究中确定的候选因子及其下游信号传导中间体在NSG模型中诱导再激活的要求。我们以前的研究和其他人的研究表明，由于病毒基因组的异染色质化，裂解病毒基因表达在CMV潜伏期受到抑制。此外，我们已经表明，移植诱导的MCMV立即早期基因表达的再激活与表观遗传重编程有关。我们的合作者托马斯克里斯蒂博士以前的研究已经确定了抑制潜伏的单纯疱疹病毒再激活的表观遗传抑制剂。在目标2中，我们将研究这些有前途的治疗干预措施，以防止NSG模型中潜伏MCMV的再激活。最后，在目标3中，我们将研究小鼠造血祖细胞中MCMV潜伏期和分化诱导再激活的新体外模型。这种互补的体外模型对于在缺乏生物体复杂性的情况下定义分子机制将是非常有用的。完成后，我们的研究将确定导致病毒染色质表观遗传重编程的信号通路，以重新激活潜伏的MCMV，以响应移植和潜在的治疗靶点。