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Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases

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Abstract

The recent microcephaly outbreak in Brazil has been associated with Zika virus (ZIKV) infection. The current understanding of damage caused by ZIKV infection is still unclear, since it has been implicated in other neurodegenerative and developmental complications. Here, the differential proteome analysis of human mesenchymal stem cells (hMSC) infected with a Brazilian strain of ZIKV was identified by shotgun proteomics (MudPIT). Our results indicate that ZIKV induces a potential reprogramming of the metabolic machinery in nucleotide metabolism, changes in the energy production via glycolysis and other metabolic pathways, and potentially inhibits autophagy, neurogenesis, and immune response by downregulation of signaling pathways. In addition, proteins previously described in several brain pathologies, such as Alzheimer’s disease, autism spectrum disorder, amyotrophic lateral sclerosis, and Parkinson’s disease, were found with altered expression due to ZIKV infection in hMSC. This potential link between ZIKV and several neuropathologies beyond microcephaly is being described here for the first time and can be used to guide specific follow-up studies concerning these specific diseases and ZIKV infection.

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Acknowledgements

The authors would like to thank Dr. E. Durigon, ICB/USP, for supplying the ZIKV strain. PMR is a 1A CNPq research fellow. APMV and TFT acknowledges postdoctoral fellowship support by CNPq/HCPA.

Funding

This work was supported by the Brazilian funding agencies Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES), FAPERGS, Edital MCTIC/FNDCT-CNPq/ MEC-CAPES/ MS-Decit / No 14/2016, project 440763/2016-9. The study was also supported by NIH grants NIH/NIHGM P41 GM103533-22 and NIH/NIMH 5 R01 MH067880-14 (to JRY).

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Authors and Affiliations

  1. Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Walter O. Beys-da-Silva & Lucélia Santi

  2. Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Walter O. Beys-da-Silva, Rafael L. Rosa, Lucélia Santi, Markus Berger, Paula Terraciano, Elizabeth O. Cirne-Lima & Jorge A. Guimarães

  3. Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Rafael L. Rosa & Jorge A. Guimarães

  4. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA

    Sung Kyu Park & John R. Yates III

  5. Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Alexandre R. Campos

  6. Centro de Cardiologia Experimental, Instituto de Cardiologia/Fundação Universitária de Cardiologia, Porto Alegre, RS, Brazil

    Ana Paula M. Varela & Thais F. Teixeira

  7. Departamento de Microbiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Paulo M. Roehe

  8. Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    André Quincozes-Santos & Diogo O. Souza

  9. Programa de Pós-Graduação em Ginecologia e Obstetrícia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Elizabeth O. Cirne-Lima

  10. Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Elizabeth O. Cirne-Lima

Authors
  1. Walter O. Beys-da-Silva
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  2. Rafael L. Rosa
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  3. Lucélia Santi
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  4. Markus Berger
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  15. Jorge A. Guimarães
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Corresponding authors

Correspondence to Walter O. Beys-da-Silva or Jorge A. Guimarães.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study was approved by the institutional research ethics committee of Hospital de Clínicas de Porto Alegre (Federal University of Rio Grande do Sul) under protocol # 2018-0059.

Additional information

Walter O. Beys-da-Silva, Rafael L. Rosa, and Lucélia Santi contribute equally for the manuscript.

Electronic Supplementary Material

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Supplementary Figure 1

PI3K-AKT signaling pathway affected by ZIKV infection in hMSC. Green rectangle: protein down-regulated in ZIKV infection. (PDF 58 kb)

Supplementary Figure 2

mTOR signaling pathway affected by ZIKV infection in hMSC. Green rectangle: proteins down-regulated in ZIKV infection; red rectangle: protein up-regulated in ZIKV infection. (PDF 40 kb)

Supplementary Figure 3

Phosphatidylinositol signaling system affected by ZIKV infection in hMSC. Green rectangle: proteins down-regulated in ZIKV infection. (PDF 177 kb)

Supplementary Table 1

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Supplementary Table 2

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Supplementary Table 3

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Beys-da-Silva, W.O., Rosa, R.L., Santi, L. et al. Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases. Mol Neurobiol 56, 4708–4717 (2019). https://doi.org/10.1007/s12035-018-1417-x

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