Allogeneic Transplantation Induces Expression of Cytomegalovirus Immediate-Early Genes In Vivo: a Model for Reactivation from Latency

Hummel, Mary; Zhang, Zheng; Yan, Shi; Plaen, Isabelle G. De; Golia, Piyush; Varghese, Thomas K.; Thomas, Gail D.; Abecassis, Michael

doi:10.1128/jvi.75.10.4814-4822.2001

Cited by 110 publications

(152 citation statements)

References 78 publications

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“…In this regard, the major cytokines of the innate immune system may have a role. There is some evidence in models of solid organ transplantation that TNFα can reverse latency back to viral replication (Docke et al, 1994;Hummel et al, 2001). On the other hand, IL-1β has been shown in bone marrow stromal cells to inhibit viral replication and perhaps induce latency (Iwata et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Listman¹,

Race²,

Walker-Kopp³

et al. 2008

Molecular Immunology

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The immediate early (IE) proteins of human cytomegalovirus (hCMV) have diverse roles in directing viral and host cell transcription. Among these is the ability of IE2 to induce transcription of the IL1B gene that codes for IL-1β in monocytes. This function is partially explained by interaction between IE2 and the host cell transcription factor Spi-1/PU.1 (Spi-1). We now show that maximal IE2 function also depends on productive interactions localizing to two C/EBP sites on the IL1B promoter suggesting either bi-or tri-molecular interactions between IE2, Spi-1 and C/EBPβ at two different locations on the promoter. The IE2 interaction region on Spi-1 was previously mapped to the DNAbinding ETS domain and overlaps the region of Spi-1 that interacts with the transcription factor C/ EBPβ, a factor known to be critical for the induction of IL1B in response to Toll/IL-1 receptor (TIR) family signal transduction. The Spi-1 interacting region of IE2 maps to amino acids 315-328, a sequence that also interacts with the bZIP domain of C/EBPβ. An expression vector coding for amino acids 291-364 of IE2 can suppress LPS induction of a cotransfected IL1B enhancer-promoter fragment in a monocyte cell line. This inhibition is likely the result of competition between Spi-1 and C/EBPβ, thus blunting gene induction.

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Section: Discussionmentioning

confidence: 99%

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Listman¹,

Race²,

Walker-Kopp³

et al. 2008

Molecular Immunology

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“…In this model, transplantation of latently infected kidneys into allogeneic recipients induced IE gene expression and epigenetic reprogramming of the MIEP within 48 h (Hummel et al, 2001;Liu et al, 2013). In addition, allogeneic transplantation induced expression of a lacZ reporter transgene under the control of the HCMV MIEP (MIEP-lacZ) (Hummel et al, 2001). Although TNF was sufficient to induce both MCMV IE gene expression and the HCMV MIEP-lacZ reporter, it was not required to activate IE gene expression in response to allogeneic transplantation in either of these models (Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…However, due to the species specificity of HCMV, it has not been possible to test this hypothesis in the context of organ transplantation. Murine cytomegalovirus (MCMV) is very similar to HCMV in many important ways, including: (i) ability to establish latency and to reactivate; (ii) hierarchical regulation of viral gene expression; (iii) structure, function and organization of the major immediate early (IE) genes (Keil et al, 1987a, b;Meier & Stinski, 2013;Stenberg et al, 1984); (iv) repression of IE gene expression during latency by heterochromatinization of viral genomes (Grzimek et al, 2001;Hummel & Abecassis, 2002;Hummel et al, 2001;Kurz et al, 1999;Liu et al, 2008;Reeves & Sinclair, 2013;Reeves et al, 2005;Seckert et al, 2013); (v) the presence of similar regulatory elements (e.g. NF-k B, AP-1, Sp1 and CREB/ATF binding sites) in the viral IE enhancers Meier & Stinski, 2013); and (vi) (re)activation of the MIEP and/or IE transcription in response to inflammatory mediators or allogeneic stimulation (Döcke et al, 1994;Fietze et al, 1994;Huang et al, 2012;Hummel & Abecassis, 2002;Hummel et al, 2001;Kew et al, 2014;Lee et al, 2004;Liu et al, 2013;O'Connor & Murphy, 2012;Prösch et al, 1995;Reeves & Compton, 2011;Simon et al, 2005;Stein et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Liu

Jie

Zhang

et al. 2016

Journal of General Virology

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Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-k B. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-k B transcription factor family and we demonstrate that canonical NF-k B (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1b, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.

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“…Zhuravskaya et al have shown that CMV infected bone marrow progenitor cells retain their ability to proliferate and differentiate. 5 They suggest that bone marrow progenitor cells can acquire CMV DNA and that this DNA can persist for an extensive period of time. The virus can create a pool of infected bone marrow progenitor cells that create a reservoir of latent virus.…”

Section: Introductionmentioning

confidence: 99%

CMV Infection in Pregnancy

Goh¹,

Sauvage²

2010

Donald School Journal of Ultrasound in Obstetrics and Gynecology

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Cytomegalovirus (CMV) is a common and serious congenital infection affecting between 1 to 4% of newborns. Congenital infections can occur after both primary and recurrent maternal infections and are the major cause of childhood deafness, visual impairment, mental retardation and motor spastic or convulsive syndromes. Ultrasound findings including IUGR, ventriculomegaly, brain and hepatic and bowel calcifications, polyhydramnios, hydrops fetalis and pleural effusions are helpful and can aid in the prenatal diagnosis and followup of congenital CMV infection. CMV hyperimmunoglobulin is safe, and may be an effective treatment to minimize the morbidity and mortality of fetal CMV disease. There is ongoing research into the development of an effective vaccine for the prevention of CMV infection during pregnancy. Objectives Understand why CMV is an important cause of congenital injections Understand the role of ultrasound in the diagnosis of intrauterine CMV infections Understand the possible treatment options for a fetus infected with CMV

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Allogeneic Transplantation Induces Expression of Cytomegalovirus Immediate-Early Genes In Vivo: a Model for Reactivation from Latency

Cited by 110 publications

References 78 publications

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

CMV Infection in Pregnancy

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