Altered Expression of Extracellular Matrix in Human-Cytomegalovirus-Infected Cells and a Human Artery Organ Culture Model to Study Its Biological Relevance

Schaarschmidt, Peter; Reinhardt, Barbara; Michel, Detlef; Vaida, Bianca; Mayr, Klaus; Lüske, Anke; Baur, Regine; Gschwend, Jürgen E.; Kleinschmidt, K.; Kountidis, Margaritis; Wenderoth, U. K.; Voisard, Rainer; Mertens, Thomas

doi:10.1159/000053972

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…While HCMV suppresses the transcription and expression of components of the extracellular matrix in productive infection, preexisting components appear to persist (28,47). The Powerblot detects high levels of fibronectin in infected cells, consistent with the extracellular matrix surviving infection.…”

Section: Discussionmentioning

confidence: 80%

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

Stanton¹,

McSharry²,

Rickards³

et al. 2007

J Virol

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Human cytomegalovirus (HCMV) is a clinically important herpesvirus associated with severe disease following congenital infection and in immunocompromised individuals. As a herpesvirus, primary infection is accompanied by lifelong persistence during which the infection must be controlled by continuous host immune surveillance. HCMV has the largest genome of any characterized human virus (ϳ236 kb) and is predicted to encode on the order of 165 potential open reading frames (15). Systematic deletion of individual open reading frames from the Towne strain revealed that only 45 are essential for virus replication in vitro; thus, accessory genes account for most of the HCMV coding capacity (16). While the functions of most of these genes have not been determined, a significant number have been implicated in the targeting of both the innate and adaptive host immune responses (40). HCMV has also recently been shown to express microRNAs during productive infection that also have the potential to modulate host cell gene expression (17,21,43). A high-throughput proteomic approach was used in this study with a view to providing further insight into how the virus may modulate its host cell.HCMV replicates slowly in permissive human fibroblasts, with gene expression conventionally being divided into three phases: immediate-early (IE), early, and late (reviewed in reference 40). Early-phase transcription precedes viral DNA replication (initiates at 16 to 24 h postinfection [hpi]), with significant virus production detected from 72 hpi and peaking at approximately 144 hpi. Productive HCMV infection is associated with an overall stimulation of both cellular transcription and translation (50). Virion binding (13, 59), release of virion tegument proteins following virion fusion (6, 36), and de novo expression of powerful transcriptional regulators (most notably, IE2 and IE1) during infection all modulate cellular gene expression. Following infection, while cellular proteins associated with DNA metabolism are induced, host cell cyclins are dysregulated and licensing of host cell DNA replication is inhibited, resulting in a "pseudo-G 1 " environment compatible with efficient virus DNA replication (3,5,25). Microarray experiments have proved highly informative in revealing the dynamic regulation of steady-state levels of cellular transcripts, both positively and negatively, during the course of infection (7,26,48,65,66). HCMV is known not only to regulate transcriptional initiation but also to control RNA processing (1,9,14,20,35,63), translation, and posttranslational modification and protein trafficking (31,34,44,54,61). The result of many of these processes is liable to be an alteration of host cell protein levels.

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Section: Discussionmentioning

confidence: 80%

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

Stanton¹,

McSharry²,

Rickards³

et al. 2007

J Virol

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“…In addition, CMV modifies a number of other cellular factors involved in angiogenesis and wound repair processes including adhesion molecules (ICAM-1, VCAM-1, VAP-1, and E-selectin,) and growth factors and receptors (TGF-β, PDGF-AA, VEGF, and PDGFR) (Shahgasempour et al 1997;Burns et al 1999;Zhou et al 1999;Inkinen et al 2003;Helantera et al 2005;Inkinen et al 2005;Reinhardt et al 2005a;Reinhardt et al 2005b;Helantera et al 2006). In addition, increased matrix metalloproteinase (MMP)-2 activity is observed in HCMV infected cells in conjunction with a reduction in matrix gene expression, resulting in a malleability to SMC migration, an alteration in vessel remodeling which promotes a vasculopathy (Schaarschmidt et al 1999;Reinhardt et al 2006). The upregulation of agents that initiate endothelial adhesion and those that promote wound healing provides a means for CMV to enhance the adherence and infiltration of inflammatory cells that drive vascular disease.…”

Section: In Vitro Models Of Hcmv Mediated Wound Healing and Angiogenesismentioning

confidence: 99%

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Streblow

Dumortier

Moses

et al. 2008

Current Topics in Microbiology and Immunology

108

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Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune-mediated injury followed by inflammation and subsequent smooth muscle cell (SMC) migration from the vessel media to the intima and proliferation that culminates in vessel narrowing. A number of epidemiological and animal studies have demonstrated that CMV significantly accelerates TVS and chronic rejection (CR) in solid organ allografts. In addition, treatment of human recipients and animals alike with the antiviral drug ganciclovir results in prolonged survival of the allograft indicating that CMV replication is a requirement for acceleration of disease. However, although virus persists in the allograft throughout the course of disease, the number of directly infected cells does not account for the global effects that the virus has on the acceleration of TVS and CR. Recent investigations of up-and down-regulated cellular genes in infected allografts in comparison to native heart has demonstrated that Rat-CMV (RCMV) up-regulates genes involved in wound healing (WH) and angiogenesis (AG). Consistent with this result, we have found that supernatants from HCMV infected cells (HCMV secretome) induce WH and AG using in vitro models. Taken together these findings suggest that one mechanism for HCMV acceleration of TVS is mediated through induction of secreted cytokines and growth factors from virus-infected cells that promote WH and AG in the allograft, resulting in the acceleration of TVS. We review here the ability of CMV infection to alter the local environment by producing cellular factors that act in a paracrine fashion to enhance WH and AG processes associated with the development of vascular disease, which accelerates chronic allograft rejection.

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“…Previous studies by us and by others have demonstrated the applicability of ex vivo organ cultures for the analysis of viral tropism within preserved 3-dimensional tissue structures in skin, lung, intestinal, arterial, cervical, and neuronal tissues (6,17,33,35,57). In the present study, we have employed a novel decidual organ culture for the ex vivo modeling of HCMV infection in the maternal-fetal interface.…”

mentioning

confidence: 90%

Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture

Weisblum

Panet

Zakay‐Rones

et al. 2011

J Virol

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Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the ex vivo modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3-to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection-providing a mechanistic basis for their clinical use in prenatal prevention. The ex vivo-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.

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Altered Expression of Extracellular Matrix in Human-Cytomegalovirus-Infected Cells and a Human Artery Organ Culture Model to Study Its Biological Relevance

Cited by 9 publications

References 41 publications

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture

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