Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases
- 692 Downloads
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.
KeywordsZika virus Brain diseases Human mesenchymal stem cells Proteome Microcephaly
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.
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).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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.
- 1.França GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD et al (2016) Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 388(10047):891–897. https://doi.org/10.1016/S0140-6736(16)30902-3 CrossRefPubMedGoogle Scholar
- 4.Beys-da-Silva WO, Santi L, Berger M, Calzolari D, Passos DO, Guimarães JA, Moresco JJ, Yates JR (2014) Secretome of the biocontrol agent Metarhizium anisopliae induced by the cuticle of the cotton pest Dysdercus peruvianus reveals new insights into infection. J Proteome Res 13:2282–2296. https://doi.org/10.1021/pr401204y CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Olmo IG, Carvalho TG, Costa VV, Alves-Silva J, Ferrari CZ, Izidoro-Toledo TC, da Silva JF, Teixeira AL et al (2017) Zika virus promotes neuronal cell death in a non-cell autonomous manner by triggering the release of neurotoxic factors. Front Immunol 8:1016. https://doi.org/10.3389/fimmu.2017.01016 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Xu T, Venable JD, Park SK, Cociorva D, Lu B, Liao L et al (2006) ProLuCID, a fast and sensitive tandem mass spectra-based protein identification program. Mol Cell Proteomics 5:S174Google Scholar
- 23.Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT et al (2017) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 45:D362–D368. https://doi.org/10.1093/nar/gkw937 CrossRefPubMedGoogle Scholar
- 28.Caires-Júnior LC, Goulart E, Melo US, Araujo BHS, Alvizi L, Soares-Schanoski A, de Oliveira DF, Kobayashi GS et al (2018) Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells. Nat Commun 9(1):475. https://doi.org/10.1038/s41467-017-02790-9. CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Nakajima S, Kitamura M (2013) Bidirectional regulation of NF-kappaB by reactive oxygen species: a role of unfolded protein response. Free Radic Biol Med 65:162–174. https://doi.org/10.1016/j.freeradbiomed.2013.06.020 CrossRefPubMedGoogle Scholar
- 33.Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255. https://doi.org/10.1002/glia.21094 CrossRefPubMedGoogle Scholar
- 36.Qimron U, Tabor S, Richardson CC (2010) New details about bacteriophage T7-host interactions. Microbe 5(3):117–122Google Scholar
- 43.Sadleir KR, Vassar R (2012) Cdk5 protein inhibition and Aβ42 increase bace1 protein level in primary neurons by a posttranscriptional mechanism implications of cdk5 as a therapeutic target for Alzheimer disease. J Biol Chem 287(10):7224–7235. https://doi.org/10.1074/jbc.M111.333914. CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Sontag JM, Nunbhakdi-Craig V, White CL, Halpain S, Sontag E (2012) The protein phosphatase pp2a/bα binds to the microtubule-associated proteins Tau and MAP2 at a motif also recognized by the kinase Fyn: implications for tauopathies. J Biol Chem 287(18):14984–14993. https://doi.org/10.1074/jbc.M111.338681 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Zelenaia O, Schlag BD, Gochenauer GE, Ganel R, Song W, Beesley JS, Grinspan JB, Rothstein JD et al (2000) Epidermal growth factor receptor agonists increase expression of glutamate transporter GLT-1 in astrocytes through pathways dependent on phosphatidylinositol 3-kinase and transcription factor NF-kappaB. Mol Pharmacol 57:667–678. https://doi.org/10.1124/mol.57.4.667 CrossRefPubMedGoogle Scholar
- 49.Janssens S, Schotsaert M, Karnik R, Balasubramaniam V, Dejosez M, Meissner A, García-Sastre A, Zwaka TP (2018) Zika virus alters DNA methylation of neural genes in an organoid model of the developing human brain. mSystems 3(1):e00219–e00217. https://doi.org/10.1128/mSystems.00219-17 CrossRefPubMedPubMedCentralGoogle Scholar