Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models

Egilmezer E, Hamilton ST, Lauw G, Follett J, Sonntag E, Schütz M, Marschall M, Rawlinson WD (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Viruses MDPI

Book Volume: 16

Article Number: 918

Journal Issue: 6

DOI: 10.3390/v16060918

Abstract

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.

Authors with CRIS profile

Eric Sonntag Institute of Clinical and Molecular Virology Martin Schütz Institute of Clinical and Molecular Virology Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Involved external institutions

Prince of Wales Hospital (POWH) AU Australia (AU) University of New South Wales (UNSW) AU Australia (AU)

How to cite

APA:

Egilmezer, E., Hamilton, S.T., Lauw, G., Follett, J., Sonntag, E., Schütz, M.,... Rawlinson, W.D. (2024). Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models. Viruses, 16(6). https://doi.org/10.3390/v16060918

MLA:

Egilmezer, Ece, et al. "Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models." Viruses 16.6 (2024).

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