Cytomegalovirus DNA in arterial walls of patients with atherosclerosis

Melnick, Joseph L.; Hu, Changzhi; Burek, Joyce; Adam, Ervín; DeBakey, Michael E.

doi:10.1002/jmv.1890420213

Cited by 172 publications

(109 citation statements)

References 12 publications

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“…HCMV infection has been associated with several forms of vascular pathology including transplantation-associated atherosclerosis (Grattan et al, 1989;Normann et al, 1991;Koskinen et al, 1993;Skowronski et al, 1993;Lautenschlager et al, 1997a), restenosis after balloon angioplasty (Speir et al, 1994;Zhou et al, 1996) and even the development of native atherosclerotic lesions (Hendrix et al, 1990;Melnick et al, 1994;Horvath et al, 2000;Streblow et al, 2001;Levi, 2001). However, the pathogenic mechanisms by which HCMV infection contributes to these processes remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of intercellular adhesion molecule-1 by the human cytomegalovirus transactivators IE2p86 and pp71 is mediated via an Sp1-binding site

Kronschnabl¹,

Stamminger²

2003

Journal of General Virology

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Human cytomegalovirus (HCMV) infection of transplant recipients is frequently associated with allograft vasculopathy and rejection. One potential mechanism is vascular injury from HCMVtriggered, immunologically mediated processes. HCMV infection has been shown to increase the expression of intercellular adhesion molecule-1 (ICAM-1). The objective of this study was to determine the molecular basis of HCMV-enhanced ICAM-1 gene expression. Transient transfection experiments identified the IE2p86 protein as a potent activator of the ICAM-1 promoter. The tegument protein pp71 showed a strong synergistic effect on IE2p86-mediated ICAM-1 promoter activation. Mutagenesis experiments defined a DNA element from 2110 to 242 relative to the transcription start site as responsive for IE2p86. Further point mutations within this DNA element identified an Sp1-binding site that was essential for strong synergistic activation by IE2p86 and pp71. To confirm the activation of ICAM-1 gene expression, human fibroblasts (HFF) as well as endothelial cells (HUVEC) were infected with recombinant IE2p86-and pp71-expressing baculoviruses, respectively. In FACS analysis, a synergistic induction of ICAM-1 was detectable when cells were co-infected with the two recombinant baculoviruses. These findings clearly demonstrate that IE2p86 and pp71 are crucial regulatory factors for HCMV-induced ICAM-1 upregulation. INTRODUCTIONHuman cytomegalovirus (HCMV), a b-herpesvirus, is a ubiquitous human pathogen with a prevalence of infection in the adult population of 50-90 %. Although HCMV rarely causes severe disease on primary infection in immunocompetent people, it represents a highly pathogenic agent for immunosuppressed patients such as transplant recipients, as well as newborns, and establishes lifelong persistence in the infected host (Alford & Britt, 1990). So far, the exact site of latency is still uncertain; monocytes, haematopoietic precursor cells and endothelial cells have been discussed as potential reservoirs for latent HCMV (Fish et al., 1995;Sindre et al., 1996).Recent evidence suggests that HCMV not only causes acute infection in transplanted patients but may also be associated with extensive transplant vasculopathy, ultimately leading to chronic allograft rejection (Grattan et al., 1989;Skowronski et al., 1993;Koskinen et al., 1993;Lautenschlager et al., 1997a;Schnitzler et al., 1997;Borchers et al., 1999). One of the molecular mechanisms underlying the acceleration of vascular disease processes by HCMV infection may be enhancement of transplant immunogenicity. Several studies indicate that this involves the HCMV-induced upregulation of cellular adhesion molecules, which augments the adherance and infiltration of inflammatory cells that are capable of promoting vascular disease (Einsele et al., 1994;Lemstrom et al., 1995;Steinhoff et al., 1995;Koskinen et al., 1996;Yilmaz et al., 1996; Martelius et al., 1998;Waldman et al., 1998;Lautenschlager et al., 1999;The et al., 2001). For instance, cell culture experiments have demonstrated that...

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Section: Discussionmentioning

confidence: 99%

Synergistic induction of intercellular adhesion molecule-1 by the human cytomegalovirus transactivators IE2p86 and pp71 is mediated via an Sp1-binding site

Kronschnabl¹,

Stamminger²

2003

Journal of General Virology

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“…CMV infection causes EC activation with procoagulant effects, increasing the risk of vascular thrombosis (133,(135)(136)(137)(138)(139). In vitro, CMV infection of ECs induces platelet aggregation and adherence and expression of von Willebrand factor (vWF), ICAM1 and VCAM1.…”

Section: Procoagulant Effectsmentioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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“…49 -51 Such activation of plaque macrophages may reflect chronic infection of the arterial wall, 24,[52][53][54][55][56][57][58][59] or it may be the result of their interaction with oxidized or otherwise-modified lipoproteins. 60,61 To further explore markers of infection in atherosclerosis, we also measured the level of PCT, which was increased in patients with PAD.…”

Section: Erren Et Al Inflammation Cad and Pad 2359mentioning

confidence: 99%