PMID- 36609616 OWN - NLM STAT- MEDLINE DCOM- 20230110 LR - 20230213 IS - 1432-8798 (Electronic) IS - 0304-8608 (Linking) VI - 168 IP - 2 DP - 2023 Jan 7 TI - MEK/ERK activation plays a decisive role in Zika virus morphogenesis and release. PG - 47 LID - 10.1007/s00705-022-05632-2 [doi] AB - 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. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature. FAU - Valencia, Hugo Jose AU - Valencia HJ AUID- ORCID: 0000-0001-9272-7095 AD - Grupo de Transducao de Sinal/Flavivirus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. hugo.valencia@untrm.edu.pe. AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. hugo.valencia@untrm.edu.pe. AD - Laboratorio de Fisiologia Molecular, Instituto de Investigacion en Ganaderia y Biotecnologia (IGBI), Universidad Nacional Toribio Rodriguez de Mendoza de Amazonas (UNTRM), Chachapoyas, Amazonas, Peru. hugo.valencia@untrm.edu.pe. FAU - Mendonca, Diogo Correa AU - Mendonca DC AD - Grupo de Transducao de Sinal/Flavivirus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. FAU - Marinho, Paula Eillanny Silva AU - Marinho PES AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. FAU - Henriques, Lethicia Ribeiro AU - Henriques LR AD - Grupo de Transducao de Sinal/Flavivirus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. AD - Nucleo de Apoio Tecnico ao Ensino, Pesquisa e Extensao-Instituto de Ciencias Ambientais, Quimicas e Farmaceuticas-Universidade Federal de Sao Paulo, Diadema, SP, Brazil. FAU - Drumond, Betania Paiva AU - Drumond BP AUID- ORCID: 0000-0002-4049-4055 AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. FAU - Bonjardim, Claudio Antonio AU - Bonjardim CA AD - Grupo de Transducao de Sinal/Flavivirus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. AD - Laboratorio de Virus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. LA - eng GR - CBB-APQ-01670-11/Fundacao de Apoio a Pesquisa do Estado de Minas Gerais (FAPEMIG)/ GR - CBB-AUC-00071-15/Fundacao de Apoio a Pesquisa do Estado de Minas Gerais (FAPEMIG)/ GR - CBB-APQ-04178-17/FAPEMIG/PPSUS (Pesquisa Para o Servico Unico de Saude)/ GR - CBB-APQ-03360-17/FAPEMIG/PPSUS (Pesquisa Para o Servico Unico de Saude)/ GR - 88882.348380/2010/Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/ GR - 001/Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/ PT - Journal Article DEP - 20230107 PL - Austria TA - Arch Virol JT - Archives of virology JID - 7506870 RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Animals MH - Chlorocebus aethiops MH - Child MH - Humans MH - *Zika Virus/genetics MH - *Zika Virus Infection MH - Vero Cells MH - *Yellow Fever/genetics MH - Extracellular Signal-Regulated MAP Kinases MH - Mitogen-Activated Protein Kinase Kinases MH - Virus Replication/physiology MH - *Flavivirus EDAT- 2023/01/08 06:00 MHDA- 2023/01/11 06:00 CRDT- 2023/01/07 16:40 PHST- 2022/05/18 00:00 [received] PHST- 2022/10/05 00:00 [accepted] PHST- 2023/01/07 16:40 [entrez] PHST- 2023/01/08 06:00 [pubmed] PHST- 2023/01/11 06:00 [medline] AID - 10.1007/s00705-022-05632-2 [pii] AID - 10.1007/s00705-022-05632-2 [doi] PST - epublish SO - Arch Virol. 2023 Jan 7;168(2):47. doi: 10.1007/s00705-022-05632-2.