Human cytomegalovirus utilises cellular dual-specificity tyrosine phosphorylation-regulated kinases during placental replication
Hamilton ST, Hutterer C, Egilmezer E, Steingruber M, Milbradt J, Marschall M, Rawlinson WD (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 72-73
Pages Range: 10-19
DOI: 10.1016/j.placenta.2018.10.002
Abstract
Introduction: Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation and in severe cases fetal and neonatal death. Fetal injury may be caused indirectly by the placental response to infection. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) have recently been identified as critical kinases for HCMV replication. In this study we provide first evidence that DYRK1A and DYRK1B are utilised during HCMV placental replication. Methods: DYRK expression was investigated in AD169-and Merlin-infected TEV-1 trophoblast cells, ex vivo placental explants and naturally infected clinical placentae by immunofluorescence, western blot, co-immunoprecipitation and RT-qPCR. Results: HCMV-infected placental cells showed accumulation and re-localisation of DYRK1A and DYRK1B protein to areas of cytoplasmic virion assembly complexes and nuclear viral replication compartments, respectively. This accumulation was a result of upregulated DYRK1A/B protein expression with HCMV inducing up to a 5.3fold increase in DYRK1A and up to a 4.7-fold increase in DYRK1B protein, relative to mock-infected TEV-1 cells (p < 0.0001). Increased DYRK protein expression was correlated with DYRK1A/B mRNA upregulation, with HCMV-infected cells showing up to a 3.7-fold increase and 2.9-fold increase in DYRK1A and DYRK1B mRNA levels respectively (p < 0.05). Protein-protein interactions were detected between DYRK1A/1B complexes and HCMV immediate early IE2p86, early pp65 and pUL44 and late pp150 proteins. Treatment of HCMV-infected TEV-1 cells and placental explants with DYRK inhibitors significantly inhibited HCMV replication (p < 0.05) indicating these cellular kinases are required during HCMV placental replication. Conclusion: HCMV modulates cellular DYRKs during placental replication which may have implications for congenital HCMV pathogenesis and represent promising antiviral targets.
Authors with CRIS profile
Mirjam Steingruber
Institute of Clinical and Molecular Virology
Jens Milbradt
Medizinische Fakultät
Manfred Marschall
Lehrstuhl für Klinische und Molekulare Virologie
Involved external institutions
Australia (AU)How to cite
APA:
Hamilton, S.T., Hutterer, C., Egilmezer, E., Steingruber, M., Milbradt, J., Marschall, M., & Rawlinson, W.D. (2018). Human cytomegalovirus utilises cellular dual-specificity tyrosine phosphorylation-regulated kinases during placental replication. Placenta, 72-73, 10-19. https://dx.doi.org/10.1016/j.placenta.2018.10.002
MLA:
Hamilton, Stuart T., et al. "Human cytomegalovirus utilises cellular dual-specificity tyrosine phosphorylation-regulated kinases during placental replication." Placenta 72-73 (2018): 10-19.
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