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Zika Virus Strains and Dengue Virus Induce Distinct Proteomic Changes in Neural Stem Cells and Neurospheres

Abstract

Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential viral molecular targets have not been fully elucidated. Here we explore the proteomic alterations induced by ZIKV by comparing the Brazilian (Br ZIKV) and the African (MR766) viral strains, in addition to comparing them to the molecular responses to the Dengue virus type 2 (DENV). Neural stem cells (NSCs) derived from induced pluripotent stem (iPSCs) were cultured both as monolayers and in suspension (resulting in neurospheres), which were then infected with ZIKV (Br ZIKV or ZIKV MR766) or DENV to assess alterations within neural cells. Large-scale proteomic analyses allowed the comparison not only between viral strains but also regarding the two- and three-dimensional cellular models of neural cells derived from iPSCs, and the effects on their interaction. Altered pathways and biological processes were observed related to cell death, cell cycle dysregulation, and neurogenesis. These results reinforce already published data and provide further information regarding the biological alterations induced by ZIKV and DENV in neural cells.

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Data Availability

The proteomic datasets generated for this study can be found in the PRIDE proteomics data repository (https://www.ebi.ac.uk/pride/archive/) with the accession numbers PXD026825 and PXD026909.

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Acknowledgements

The authors thank Gabriela Vitoria, Ismael Gomes, Paulo Baldasso, and Erick Loiola for their excellent technical support and Bradley Smith, MSc for the critical comments and English review support during the process.

Funding

Financial support was provided by the São Paulo Research Foundation (D. G. J., J. M. N., G. S. Z., C. B. T., J. S. C., A. S. L. M. A. and D. M. S. are supported by FAPESP grant numbers 2014/14881-1, 2014/21035-0, 2017/25055-3, 2018/25439–9, 2018/14666–4, 2020/10282-7, 2017/25588–1, 2019/00098-7), and the National Council of Scientific and Technological Development (CNPq), in addition to intramural grants from D’Or Institute for Research and Education.

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J. M. N., P. P. G., S. K. R., and D. M. S. conceived and designed the study. D. J. G. and J. M. N. performed in silico proteomic analyses. J. M. N. and J. S. C. performed the mass spectrometry experiments. G. S. Z. performed the pathway analysis and interpretation. P. P. G., C. S. G. P., K. K., J. A. S., A. S. L. M. A., C. B. T., L. M. H., G. F. S., S. P. M., and F. C. cultured iPS cells and/or virus strains, performed cell-based assays and/or infection, and contributed to discussion. A. T. and J. L. P. M. performed the data interpretation. D. J. G. and J. M. N. interpreted the data, wrote, edited, and revised the manuscript. D. M. S. and S. K. R. coordinated the study. All authors contributed to the final version of the manuscript.

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Correspondence to Stevens K. Rehen or Daniel Martins-de-Souza.

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Nascimento, J.M., Gouvêa-Junqueira, D., Zuccoli, G.S. et al. Zika Virus Strains and Dengue Virus Induce Distinct Proteomic Changes in Neural Stem Cells and Neurospheres. Mol Neurobiol 59, 5549–5563 (2022). https://doi.org/10.1007/s12035-022-02922-3

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Keywords

  • Neurodevelopment
  • Microcephaly
  • Flaviviridae
  • Neural cells
  • iPS