MEK/ERK activation plays a decisive role in Zika virus morphogenesis and release

Valencia, H. J., Mendonça, D. C. , Marinho, P. E. S., Henriques, L. R., Drumond, B. P. and Bonjardim, C. A. (2023) MEK/ERK activation plays a decisive role in Zika virus morphogenesis and release. Archives of Virology, 168(2), 47. (doi: 10.1007/s00705-022-05632-2) (PMID:36609616)

Abstract

Brazil has experienced an increase in outbreaks caused by flaviviruses. The high incidence of dengue fever, the morbidity of Zika in children, and the high mortality of yellow fever have affected millions in recent years. Deciphering host-virus interactions is important for treating viral infections, and the mitogen-activated protein kinases (MAPK) are an interesting target because of their role in flavivirus replication. In particular, mitogen-activated protein kinase kinase (MEK), which targets extracellular-signal-regulated kinase (ERK), is necessary for dengue and yellow fever infections. In this study, we evaluated the role of the MEK/ERK pathway and the effect of the MEK inhibitor trametinib on the Asian ZIKV strain PE243 and the prototype African ZIKV strain MR766, addressing genome replication, morphogenesis, and viral release. ZIKV infection stimulated ERK phosphorylation in Vero cells at 12 and 18 hours postinfection (hpi). Trametinib showed sustained antiviral activity, inhibiting both ZIKV strains for at least four days, and electron microscopy showed probable inhibition of ZIKV morphogenesis. ZIKV PE243 can complete one cycle in Vero cells in 14 hours; genome replication was detected around 8 hpi, intracellular viral particles at 12 hpi, and extracellular progeny at 14 hpi. Treatments at 6-hour intervals showed that trametinib inhibited late stages of viral replication, and the titration of intra- or extracellular virions showed that the treatment especially affected viral morphogenesis and release. Thus, ZIKV stimulated ERK phosphorylation during viral morphogenesis and release, which correlated with trametinib inhibiting both the signaling pathway and viral replication.

• Item Type: Articles
• Additional Information: This work was supported by grants awarded to C. A. Bonjardim: Fundação de Apoio a Pesquisa do Estado de Minas Gerais (FAPEMIG) CBB-APQ-01670-11; CBB-AUC-00071-15; FAPEMIG/PPSUS (Pesquisa Para o Serviço Único de Saúde) CBB-APQ-04178-17; CBB-APQ-03360-17; Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior (CAPES) 88882.348380/2010 and 001. C. A. Bonjardim and B. P. Drumond are research fellows of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Correa Mendonca, Dr Diogo
• Authors: Valencia, H. J., Mendonça, D. C., Marinho, P. E. S., Henriques, L. R., Drumond, B. P., and Bonjardim, C. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Archives of Virology
• Publisher: Springer
• ISSN: 0304-8608
• ISSN (Online): 1432-8798
• Published Online: 07 January 2023