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

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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.

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Acknowledgements

The authors wish to thank MD. Mauricio Nogueira for providing ZIKV MR766. We also thank our colleagues from Laboratório de Vírus, especially M.Sc. Mariana Araújo for her support and insights in the conclusion of this paper.

Funding

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).

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Authors and Affiliations

  1. Grupo de Transdução de Sinal/Flavivírus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Hugo José Valencia, Diogo Corrêa Mendonça, Lethícia Ribeiro Henriques & Cláudio Antônio Bonjardim

  2. Laboratório de Vírus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Hugo José Valencia, Diogo Corrêa Mendonça, Paula Eillanny Silva Marinho, Lethícia Ribeiro Henriques, Betânia Paiva Drumond & Cláudio Antônio Bonjardim

  3. Laboratorio de Fisiología Molecular, Instituto de Investigación en Ganadería y Biotecnología (IGBI), Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas (UNTRM), Chachapoyas, Amazonas, Peru

    Hugo José Valencia

  4. Núcleo de Apoio Técnico ao Ensino, Pesquisa e Extensão-Instituto de Ciências Ambientais, Químicas e Farmacêuticas-Universidade Federal de São Paulo, Diadema, SP, Brazil

    Lethícia Ribeiro Henriques

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  1. Hugo José Valencia
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Contributions

Cláudio Antônio Bonjardim, Betânia Paiva Drumond, and Hugo José Valencia contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Hugo José Valencia, Diogo Corrêa Mendonça, and Paula Eillanny Silva Marinho. The first draft of the manuscript was written by Hugo José Valencia, Diogo Corrêa Mendonça, and Lethícia Ribeiro Henriques, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hugo José Valencia.

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Valencia, H.J., Mendonça, D.C., Marinho, P.E.S. et al. MEK/ERK activation plays a decisive role in Zika virus morphogenesis and release. Arch Virol 168, 47 (2023). https://doi.org/10.1007/s00705-022-05632-2

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