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

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

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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.

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ESM 1

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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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Keywords

  • Zika virus
  • Brain diseases
  • Human mesenchymal stem cells
  • Proteome
  • Microcephaly