Inhibition of epidermal growth factor receptor (EGFR) expression by human cytomegalovirus correlates with an increase in the expression and binding of Wilms' Tumour 1 protein to the EGFR promoter

Jafferji, Insiya; Bain, Mark; King, Christine A.

doi:10.1099/vir.0.009670-0

Cited by 21 publications

(31 citation statements)

References 26 publications

(41 reference statements)

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“…Since the SFTPA-1 is a transcriptional indicator of EGFR (epidermal growth hormone receptor) signaling pathway [41], the reduction in SFTPA-1 expression suggests that the EGFR signaling pathway is suppressed by ILTV infection. This conclusion is consistent with the reported downregulation of EGFR functions in HCMV infected human lung [41] and foreskin fibroblastic cells [42]. Additionally, our findings are similar to a report in which the mRNA expression of SFTPA-1 declined after inoculation of influenza A virus H9N2 into chicken lung cells [43].…”

Section: Resultssupporting

confidence: 93%

Transcriptional profiling of host gene expression in chicken embryo lung cells infected with laryngotracheitis virus

et al. 2010

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BackgroundInfection by infectious laryngotracheitis virus (ILTV; gallid herpesvirus 1) causes acute respiratory diseases in chickens often with high mortality. To better understand host-ILTV interactions at the host transcriptional level, a microarray analysis was performed using 4 × 44 K Agilent chicken custom oligo microarrays.ResultsMicroarrays were hybridized using the two color hybridization method with total RNA extracted from ILTV infected chicken embryo lung cells at 0, 1, 3, 5, and 7 days post infection (dpi). Results showed that 789 genes were differentially expressed in response to ILTV infection that include genes involved in the immune system (cytokines, chemokines, MHC, and NF-κB), cell cycle regulation (cyclin B2, CDK1, and CKI3), matrix metalloproteinases (MMPs) and cellular metabolism. Differential expression for 20 out of 789 genes were confirmed by quantitative reverse transcription-PCR (qRT-PCR). A bioinformatics tool (Ingenuity Pathway Analysis) used to analyze biological functions and pathways on the group of 789 differentially expressed genes revealed that 21 possible gene networks with intermolecular connections among 275 functionally identified genes. These 275 genes were classified into a number of functional groups that included cancer, genetic disorder, cellular growth and proliferation, and cell death.ConclusionThe results of this study provide comprehensive knowledge on global gene expression, and biological functionalities of differentially expressed genes in chicken embryo lung cells in response to ILTV infections.

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Section: Resultssupporting

confidence: 93%

Transcriptional profiling of host gene expression in chicken embryo lung cells infected with laryngotracheitis virus

et al. 2010

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“…3D and E). The precipitated fractions also contained the EGFR, although in agreement with previous reports (54)(55)(56), the amount of the EGFR was reduced in CMV-infected cells, particularly in those cells infected with the strain AD169-based mutant. In contrast, the trans-Golgi compartment-resident membrane protein p230 (57) could not be precipitated, indicating that the plasma membrane remained intact during the labeling procedure and only surface proteins were exposed to biotin.…”

Section: Expression Of Ul11 Proteins During the Lytic CMV Infection Csupporting

confidence: 74%

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Gabaev

Elbasani

Ameres

et al. 2014

J Virol

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The human cytomegalovirus (CMV) UL11 open reading frame (ORF) encodes a putative type I transmembrane glycoprotein which displays remarkable amino acid sequence variability among different CMV isolates, suggesting that it represents an important virulence factor. In a previous study, we have shown that UL11 can interact with the cellular receptor tyrosine phosphatase CD45, which has a central role for signal transduction in T cells, and treatment of T cells with large amounts of a soluble UL11 protein inhibited their proliferation. In order to analyze UL11 expression in CMV-infected cells, we constructed CMV recombinants whose genomes either encode tagged UL11 versions or carry a stop mutation in the UL11 ORF. Moreover, we examined whether UL11 affects the function of virus-specific cytotoxic T lymphocytes (CTLs). We found that the UL11 ORF gives rise to several proteins due to both posttranslational modification and alternative translation initiation sites. Biotin labeling of surface proteins on infected cells indicated that only highly glycosylated UL11 forms are present at the plasma membrane, whereas less glycosylated UL11 forms were found in the endoplasmic reticulum. We did not find evidence of UL11 cleavage or secretion of a soluble UL11 version. Cocultivation of CTLs recognizing different CMV epitopes with fibroblasts infected with a UL11 deletion mutant or the parental strain revealed that under the conditions applied UL11 did not influence the activation of CMV-specific CD8 T cells. For further studies, we propose to investigate the interaction of UL11 with CD45 and the functional consequences in other immune cells expressing CD45. IMPORTANCEHuman cytomegalovirus (CMV) belongs to those viruses that extensively interfere with the host immune response, yet the precise function of many putative immunomodulatory CMV proteins remains elusive. Previously, we have shown that the CMV UL11 protein interacts with the leukocyte common antigen CD45, a cellular receptor tyrosine phosphatase with a central role for signal transduction in T cells. Here, we examined the proteins expressed by the UL11 gene in CMV-infected cells and found that at least one form of UL11 is present at the cell surface, enabling it to interact with CD45 on immune cells. Surprisingly, CMVexpressed UL11 did not affect the activity of virus-specific CD8 T cells. This finding warrants investigation of the impact of UL11 on CD45 functions in other leukocyte subpopulations.

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“…Altogether, these observations suggest that cellular differentiation is stimulated in early stages of infection and that cells tend to fuse forming syncytia as viral concentration increases or time after infection progresses. A possible explanation for this latter effect can be a distinct regulation of transcription factors such as SOX2 which is related to embryonic development and stem cell self-renewal and expression of some receptors like EGFR as well as cytoskeleton components (Jafferji et al 2009;Luo et al 2010). Nevertheless, the relevance of HCMV-induced differentiation in the context of CNS development and finding why it is reversed when viral concentration increases are a matter for further investigation.…”

Section: Discussionmentioning

confidence: 99%

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

et al. 2015

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Cytomegalovirus (CMV) is the most common cause of congenital infection in developed countries and a major cause of neurological disability in children. Although CMV can affect multiple organs, the most important sequelae of intrauterine infection are related to lesions of the central nervous system. However, little is known about the pathogenesis and the cellular events responsible for neuronal damage in infants with congenital infection. Some studies have demonstrated that neural precursor cells (NPCs) show the greatest susceptibility to CMV infection in the developing brain. We sought to establish an in vitro model of CMV infection of the developing brain in order to analyze the cellular events associated with invasion by this virus. To this end, we employed two cell lines as a permanent source of NPC, avoiding the continuous use of human fetal tissue, the human SK-N-MC neuroblastoma cell line, and an immortalized cell line of human fetal neural origin, hNS-1. We also investigated the effect of the differentiation stage in relation to the susceptibility of these cell lines by comparing the neuroblastoma cell line with the multipotent cell line hNS-1. We found that the effects of the virus were more severe in the neuroblastoma cell line. Additionally, we induced hNS-1 to differentiate and evaluated the effect of CMV in these differentiated cells. Like SK-N-MC cells, hNS-1-differentiated cells were also susceptible to infection. Viability of differentiated hNS-1 cells decreased after CMV infection in contrast to undifferentiated cells. In addition, differentiated hNS-1 cells showed an extensive cytopathic effect whereas the effect was scarce in undifferentiated cells. We describe some of the effects of CMV in neural stem cells, and our observations suggest that the degree of differentiation is important in the acquisition of susceptibility.

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Inhibition of epidermal growth factor receptor (EGFR) expression by human cytomegalovirus correlates with an increase in the expression and binding of Wilms' Tumour 1 protein to the EGFR promoter

Cited by 21 publications

References 26 publications

Transcriptional profiling of host gene expression in chicken embryo lung cells infected with laryngotracheitis virus

Transcriptional profiling of host gene expression in chicken embryo lung cells infected with laryngotracheitis virus

Expression of the Human Cytomegalovirus UL11 Glycoprotein in Viral Infection and Evaluation of Its Effect on Virus-Specific CD8 T Cells

Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state

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