The R33 G Protein-Coupled Receptor Gene of Rat Cytomegalovirus Plays an Essential Role in the Pathogenesis of Viral Infection

Beisser, Patrick S.; Vink, Cornelis; Dam, Joanne G. Van; Grauls, Gert; Vanherle, Sabina J. V.; Bruggeman, Cathrien A.

doi:10.1128/jvi.72.3.2352-2363.1998

Cited by 134 publications

(53 citation statements)

References 52 publications

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“…of 0.01. Previous studies of M78 in MCMV and homologues in rat CMV (RCMV: R78) and HCMV (UL78) have indicated that a loss of gene function resulted in replication defects in tissue culture; for the rodent counterparts a deficiency in salivary gland tropism in vivo was also observed (Beisser et al, 1998;O'Connor & Shenk, 2012;Oliveira & Shenk, 2001). Multi-step growth analysis showed that M78-LUC grew to wt MCMV levels in each cell type ( Fig.…”

Section: Recombinant M78-luc Virus Is Not Attenuated In Vitro or In Vivomentioning

confidence: 84%

Luciferase-tagged wild-type and tropism-deficient mouse cytomegaloviruses reveal early dynamics of host colonization following peripheral challenge

Farrell

Oliveira

Macdonald

et al. 2016

Journal of General Virology

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Cytomegaloviruses (CMVs) establish persistent, systemic infections and cause disease by maternal-foetal transfer, suggesting that their dissemination is a key target for antiviral intervention. Late clinical presentation has meant that human CMV (HCMV) dissemination is not well understood. Murine CMV (MCMV) provides a tractable model. Whole mouse imaging of virus-expressed luciferase has proved a useful way to track systemic infections. MCMV, in which the abundant lytic gene M78 was luciferase-tagged via a self-cleaving peptide (M78-LUC), allowed serial, unbiased imaging of systemic and peripheral infection without significant virus attenuation. Ex vivo luciferase imaging showed greater sensitivity than plaque assay, and revealed both well-known infection sites (the lungs, lymph nodes, salivary glands, liver, spleen and pancreas) and less explored sites (the bone marrow and upper respiratory tract). We applied luciferase imaging to tracking MCMV lacking M33, a chemokine receptor conserved in HCMV and a proposed anti-viral drug target. M33-deficient M78-LUC colonized normally in peripheral sites and local draining lymph nodes but spread poorly to the salivary gland, suggesting a defect in vascular transport consistent with properties of a chemokine receptor.

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Section: Recombinant M78-luc Virus Is Not Attenuated In Vitro or In Vivomentioning

confidence: 84%

Luciferase-tagged wild-type and tropism-deficient mouse cytomegaloviruses reveal early dynamics of host colonization following peripheral challenge

Farrell

Oliveira

Macdonald

et al. 2016

Journal of General Virology

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“…The mutant strain RCMVΔR33 could not be detected from the salivary glands as opposed to normal RCMV so the normal pathobiology of the infection is altered. Although a similar amount of DNA was observed in allografts of mutant RCMVΔR33‐ and normal RCMV‐infected recipients, the authors have previously shown that mutant RCMVΔR33 could not be detected in salivary glands of infected immunocompromised rats either by plaque assay or immunohistochemistry, although viral DNA could be detected up to 14 days after infection (2). Beisser et al discussed that it is possible that the ability to detect RCMV DNA in salivary glands early after infection is not the actual result of infection of salivary gland cells but instead the result of the presence of RCMV DNA‐containing circulating cells that pass through blood vessels of salivary glands (2).…”

mentioning

confidence: 87%

“…However, the mechanisms by which CMV enhances cardiac allograft arteriosclerosis are incompletely understood. In an article published in this issue, Streblow et al have investigated the role of CMV‐encoded chemokine receptors in cardiac allograft arteriosclerosis in a rat heart transplant model using a mutant strain of rat CMV (RCMV) that lacks the R33 open reading frame (RCMVΔR33) (2). The R33 chemokine receptor is a functional homologue of the HCMV encoded chemokine receptor US28.…”

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confidence: 99%

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Effect of Cytomegalovirus on Cardiac Allograft Arteriosclerosis—Indirect or Direct?

Lemström

Tikkanen

Koskinen

et al. 2005

American Journal of Transplantation

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Clinical evidence that human cytomegalovirus (HCMV) has a role in cardiac allograft arteriosclerosis comes from a study where ganciclovir treatment of heart transplant recipients delayed allograft rejection and the development of allograft arteriosclerosis (1). However, the mechanisms by which CMV enhances cardiac allograft arteriosclerosis are incompletely understood. In an article published in this issue, Streblow et al. have investigated the role of CMV-encoded chemokine receptors in cardiac allograft arteriosclerosis in a rat heart transplant model using a mutant strain of rat CMV (RCMV) that lacks the R33 open reading frame (RCMV R33) (2). The R33 chemokine receptor is a functional homologue of the HCMV encoded chemokine receptor US28. Streblow et al. have previously shown that HCMV infection of arterial smooth muscle cells (SMC) in vitro induces cellular migration that is mediated by the virally encoded chemokine receptor US28 (3).In their article, the authors show that the mutant strain RCMV R33 induces far less SMC migration than a normal RCMV strain in vitro. Also, compared to normal RCMV, the mutant strain RCMV R33 was associated with a later onset but did however, accelerate the development of cardiac allograft arteriosclerosis compared to non-infected controls. The authors showed that similar quantities of viral DNA could be observed from the allograft in mutant RCMV R33-and normal RCMV-infected recipients but the mutant RCMV R33 could not be located in the salivary glands in contrast-to-normal RCMV. Therefore, if SMC in the allograft media are heavily infected with CMV encoding US28 (in man) or R33 (in rat) or other chemokine receptors, one could think that these infected SMC would migrate to the intimal area and proliferate there causing the concentric intimal lesion seen in allograft arteriosclerosis. The findings in this study support the 'direct hypothesis' of the effect of CMV on development of cardiac allograft arteriosclerosis, that is, CMV infects SMC and causes their migration and proliferation in the vascular wall by altering the metaboly of SMC. For example, Speir et al. showed that CMV may inactivate the p53 tumor suppressor gene and CMV actively induces SMC migration in vitro (4).In our series, we have detected only a few RCMV-positive cells in allografts in vivo at any time point and the infected cells are mostly mononuclear inflammatory cells (5). Thus, we feel that CMV does not directly enhance SMC migration and proliferation to a significant extent but rather is a marked risk factor for acute rejection and has been shown to actively boost the alloimmune response. Furthermore, CMV infection-enhanced allograft arteriosclerosis may be inhibited with elevated immunosuppression, suggesting that CMV infection enhances SMC migration and allograft arteriosclerosis indirectly via strengthening the alloimmune response (6). In this article, the effect of the mutant strain RCMV R33 on acute rejection and allograft inflammation was not studied and it would have been interesting to see whether th...

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“…A low level of replication was detectable in spleen and liver suggesting that the M33 gene product plays a role in dissemination to or replication in salivary glands [76]. A similar rat CMV mutant (R33) was transported normally to the salivary glands but was unable to enter or replicate in the salivary glands [77]. A number of other genes a¡ect replication in this organ.…”

Section: Tissue Tropismmentioning

confidence: 99%

The pathogenicity of cytomegalovirus

Sweet

1999

FEMS Microbiology Reviews

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Human cytomegalovirus is ubiquitous, yet causes little illness in immunocompetent individuals. Disease is evident in immunodeficient groups such as neonates, transplant recipients and AIDS patients either following a primary infection or reactivation of a latent infection. Little is known of the mechanisms underlying the pathogenicity of the virus. The recent determination of the nucleotide sequence of both human cytomegalovirus (strain AD169) and murine cytomegalovirus (murine cytomegalovirus strain Smith) has allowed an analysis of the biological importance of several virus genes. Studies with human cytomegalovirus have indicated that many viral genes are non-essential for replication in vitro which are thus assumed to be important in the pathogenesis of the virus. This is being examined in the murine model where the role of the gene and its product in disease can be directly examined in vivo using viral mutants in which the relevant gene has been interrupted or deleted. Current information on the role of cytomegalovirus genes in tissue tropism, immune evasion, latency, reactivation from latency and damage is described.

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The R33 G Protein-Coupled Receptor Gene of Rat Cytomegalovirus Plays an Essential Role in the Pathogenesis of Viral Infection

Cited by 134 publications

References 52 publications

Luciferase-tagged wild-type and tropism-deficient mouse cytomegaloviruses reveal early dynamics of host colonization following peripheral challenge

Luciferase-tagged wild-type and tropism-deficient mouse cytomegaloviruses reveal early dynamics of host colonization following peripheral challenge

Effect of Cytomegalovirus on Cardiac Allograft Arteriosclerosis—Indirect or Direct?

The pathogenicity of cytomegalovirus

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