Rat cytomegalovirus replication in the salivary glands is exclusively confined to striated duct cells

Kloover, JS; Hillebrands, Jan Luuk; Wit, GA De; Grauls, Gert; Rozing, Jan; Bruggeman, C. A.; Nieuwenhuis, Paul

doi:10.1007/s004280000264

Cited by 16 publications

(21 citation statements)

References 41 publications

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“…3). This finding is not surprising, since previous studies had demonstrated that RCMV takes approximately 14 days to establish infection in SMG (5,6,17,26). Approximately 11% of the RCMV genes are expressed at 14 days p.i., and this number increases to nearly 25% by day 21, which includes genes expressed with IE, E, and L kinetics.…”

Section: Resultssupporting

confidence: 54%

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Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

Streblow

Cleef²,

Kreklywich

et al. 2007

J Virol

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Rat cytomegalovirus (RCMV) is a ␤-herpesvirus with a 230-kbp genome containing over 167 open reading frames (ORFs). RCMV gene expression is tightly regulated in cultured cells, occurring in three distinct kinetic classes (immediate early, early, and late). However, the extent of viral-gene expression in vivo and its relationship to the in vitro expression are unknown. In this study, we used RCMV-specific DNA microarrays to investigate the viral transcriptional profiles in cultured, RCMV-infected endothelial cells, fibroblasts, and aortic smooth muscle cells and to compare these profiles to those found in tissues from RCMV-infected rat heart transplant recipients. In cultured cells, RCMV expresses approximately 95% of the known viral ORFs with few differences between cell types. By contrast, in vivo viral-gene expression in tissues from rat heart allograft recipients is highly restricted. In the tissues studied, a total of 80 viral genes expressing levels twice above background (5,000 to 10,000 copies per g total RNA) were detected. In each tissue type, there were a number of genes expressed exclusively in that tissue. Although viral mRNA and genomic DNA levels were lower in the spleen than in submandibular glands, the number of individual viral genes expressed was higher in the spleen (60 versus 41). This finding suggests that the number of viral genes expressed is specific to a given tissue and is not dependent upon the viral load or viral mRNA levels. Our results demonstrate that the profiles, as well as the amplitude, of viral-gene expression are tissue specific and are dramatically different from those in infected cultured cells, indicating that RCMV gene expression in vitro does not reflect viral-gene expression in vivo.

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Section: Resultssupporting

confidence: 54%

“…RCMV infects a number of different cell types both in vivo and in vitro, including EC, SMC, epithelial cells, fibroblasts, and macrophages (17,28). Similar to HCMV, the RCMV genome is about 230 kbp and includes 167 predicted ORFs (29).…”

Section: Resultsmentioning

confidence: 99%

Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

Streblow

Cleef²,

Kreklywich

et al. 2007

J Virol

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“…We have utilized a rat cytomegalovirus (RCMV) infection system to model a number of human diseases associated with HCMV infections, including solid-organ transplant rejection and restenosis following angioplasty (26, 27, 29-31, 36-39, 45, 46, 56, 58, 62-64). Similar to human infection, infection of immunocompetent rats leads to a limited subclinical infection that persists lifelong in host bone marrow and columnar epithelial cells of the salivary glands (28). RCMV infection of immunocompromised rats (i.e., rats undergoing immunosuppressive treatment for the prevention of allograft rejection) leads to infection of most host tissues and organs.…”

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confidence: 99%

Cytomegalovirus MicroRNA Expression Is Tissue Specific and Is Associated with Persistence

Meyer

Grey

Kreklywich

et al. 2011

J Virol

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MicroRNAs (miRNAs) are a class of small noncoding RNAs involved in posttranscriptional regulation. miRNAs are utilized in organisms ranging from plants to higher mammals, and data have shown that DNA viruses also use this method for host and viral gene regulation. Here, we report the sequencing of the small RNAs in rat cytomegalovirus (RCMV)-infected fibroblasts and persistently infected salivary glands. We identified 24 unique miRNAs that mapped to hairpin structures found within the viral genome. While most miRNAs were detected in both samples, four were detected exclusively in the infected fibroblasts and two were specific for the infected salivary glands. The RCMV miRNAs are distributed across the viral genome on both the positive and negative strands, with clusters of miRNAs at a number of locations, including near viral genes r1 and r111. The RCMV miRNAs have a genomic positional orientation similar to that of the miRNAs described for mouse cytomegalovirus, but they do not share any substantial sequence conservation. Similar to other reported miRNAs, the RCMV miRNAs had considerable variation at their 3 and 5 ends. Interestingly, we found a number of specific examples of differential isoform usage between the fibroblast and salivary gland samples. We determined by real-time PCR that expression of the RCMV miRNA miR-r111.1-2 is highly expressed in the salivary glands and that miR-R87-1 is expressed in most tissues during the acute infection phase. Our study identified the miRNAs expressed by RCMV in vitro and in vivo and demonstrated that expression is tissue specific and associated with a stage of viral infection.MicroRNAs (miRNAs) are small noncoding RNAs involved in posttranscriptional regulation through binding to complementary sequences in target mRNAs resulting in gene silencing (4). miRNAs are ubiquitous among multicellular eukaryotic organisms, including plants and higher mammals, and have diverse roles in many different biological processes, including development, differentiation, proliferation, apoptosis, and hematopoiesis (35,51). In addition to eukaryotic miRNAs, DNA viruses, mainly of the Herpesvirus family, have been shown to encode miRNAs. Bioinformatic, sequencing, and direct cloning approaches have led to the identification of more than 140 viral miRNAs (reviewed in reference 55). The role of viral miRNAs is proposed to include the targeting of cellular genes to induce a favorable replication environment or to evade the host immune system and the targeting of their own viral genome to regulate viral gene expression during persistence or latency/reactivation (22, 55).Human cytomegalovirus (HCMV) is known to encode at least 14 miRNAs. HCMV is a ubiquitous betaherpesvirus, and primary infection results in lifelong persistent/latent infection of the host. Infection of immunocompetent hosts is generally asymptomatic, but infection of immunocompromised hosts can lead to high morbidity and mortality. HCMV has been linked to the development of atherosclerosis, arterial restenosis following angiopla...

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“…3–15 Both acinar and ductal salivary epithelial cells can be infected by hCMV. 5,10–12 After infection, hCMV can remain latent for the rest of the host’s life, maintaining the viral genome without the production of infectious virions. 16–18 The hCMVp is a frequently used enhancer/promoter in many gene transfer vectors.…”

Section: Introductionmentioning

confidence: 99%

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter

et al. 2015

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In 2012, we reported that 5 out of 11 subjects in a clinical trial (NCT00372320) administering AdhAQP1 to radiation-damaged parotid glands showed increased saliva flow rates and decreased symptoms over the initial 42 days. AdhAQP1 is a first-generation, E1-deleted, replication-defective, serotype 5 adenoviral vector encoding human aquaporin-1 (hAQP1). This vector uses the human cytomegalovirus enhancer/promoter (hCMVp). As subject peak responses were at times much longer (7–42 days) than expected, we hypothesized that the hCMVp may not be methylated in human salivary gland cells to the extent previously observed in rodent salivary gland cells. This hypothesis was supported in human salivary gland primary cultures and human salivary gland cell lines after transduction with AdhAQP1. Importantly, hAQP1 maintained its function in those cells. Conversely, when we transduced mouse and rat cell lines in vitro and submandibular glands in vivo with AdhAQP1, the hCMVp was gradually methylated over time and associated with decreased hAQP1 expression and function in vitro and decreased hAQP1 expression in vivo. These data suggest that the hCMVp in AdhAQP1was probably not methylated in transduced human salivary gland cells of responding subjects, resulting in an unexpectedly longer functional expression of hAQP1.

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Rat cytomegalovirus replication in the salivary glands is exclusively confined to striated duct cells

Cited by 16 publications

References 41 publications

Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

Cytomegalovirus MicroRNA Expression Is Tissue Specific and Is Associated with Persistence

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter

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