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Japanese Encephalitis Virus Infection Alters Both Neuronal and Astrocytic Differentiation of Neural Stem/Progenitor Cells

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Abstract

Japanese encephalitis virus (JEV) predominantly infects neurons and causes damage to the central nervous system (CNS). Neural stem/progenitor cells (NSPCs) constitute multi-potent stem cell population in postnatal/adult brain, with capacity to differentiate into neurons, astrocytes or oligodendrocytes. NSPCs are known to play a pivotal role in CNS repair mechanisms during various neurological disorders. Previous studies from our laboratory have shown that JEV infection of NSPCs depletes the stem-cell pool, which may result in impaired repair functions leading to motor and cognitive deficits in survivors. In the present study, we evaluated the effect of JEV infection on differentiation potential of NSPCs isolated from BALB/c mouse pups (Post natal day 7). Results clearly indicated that, JEV infection was more robust in undifferentiated NSPCs as compared to differentiated ones. Further, JEV infected NSPCs showed hampered differentiation and arrested migration in adherent neurosphere cultures. Interestingly, the neuronal differentiation appeared to be more severely affected by JEV as compared to astrocyte differentiation. The transcription factors involved in both neuronal and astrocyte differentiations were significantly decreased upon JEV infection. Overall, results presented in this study comprehensively provide first evidence for JEV induced alteration of neuronal and astrocyte differentiation.

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References

  • Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569

    Article  PubMed  CAS  Google Scholar 

  • Banerjee S, Crouse NR, Emnett RJ, Gianino SM, Gutmann DH (2011) Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc Natl Acad Sci U S A 108:15996–16001

    Article  PubMed  CAS  Google Scholar 

  • Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483

    Article  PubMed  CAS  Google Scholar 

  • Das S, Basu A (2008) Japanese encephalitis virus infects neural progenitor cells and decreases their proliferation. J Neurochem 106:1624–1636

    PubMed  CAS  Google Scholar 

  • Das S, Basu A (2011) Viral infection and neural stem/progenitor cell’s fate: implications in brain development and neurological disorders. Neurochem Int 59:357–366

    Article  PubMed  CAS  Google Scholar 

  • Das S, Ghosh D, Basu A (2009) Japanese encephalitis virus induce immuno-competency in neural stem/progenitor cells. PLoS One 4:e8134

    Article  PubMed  Google Scholar 

  • Das S, Chakraborty S, Basu A (2010) Critical role of lipid rafts in virus entry and activation of phosphoinositide 3′ kinase/Akt signaling during early stages of Japanese encephalitis virus infection in neural stem/progenitor cells. J Neurochem 115:537–549

    Article  PubMed  CAS  Google Scholar 

  • Diagana M, Preux PM, Dumas M (2007) Japanese encephalitis revisited. J Neurol Sci 262:165–170

    Article  PubMed  Google Scholar 

  • Emsley JG, Mitchell BD, Kempermann G, Macklis JD (2005) Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog Neurobiol 75:321–341

    Article  PubMed  CAS  Google Scholar 

  • Ensoli F, Wang H, Fiorelli V, Zeichner SL, De Cristofaro MR, Luzi G, Thiele CJ (1997) HIV-1 infection and the developing nervous system: lineage-specific regulation of viral gene expression and replication in distinct neuronal precursors. J Neurovirol 3:290–298

    Article  PubMed  CAS  Google Scholar 

  • Feuer R, Mena I, Pagarigan RR, Harkins S, Hassett DE, Whitton JL (2003) Coxsackievirus B3 and the neonatal CNS: the roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease. Am J Pathol 163:1379–1393

    Article  PubMed  CAS  Google Scholar 

  • Ghoshal A, Das S, Ghosh S, Mishra MK, Sharma V, Koli P, Sen E, Basu A (2007) Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis. Glia 55:483–496

    Article  PubMed  Google Scholar 

  • He F, Ge W, Martinowich K, Becker-Catania S, Coskun V, Zhu W, Wu H, Castro D, Guillemot F, Fan G, de Vellis J, Sun YE (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8:616–625

    Article  PubMed  CAS  Google Scholar 

  • Ito H, Nakajima A, Nomoto H, Furukawa S (2003) Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription factors Mash1 and Math1. J Neurosci Res 71:648–658

    Article  PubMed  CAS  Google Scholar 

  • Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306:343–348

    Article  PubMed  CAS  Google Scholar 

  • Kernie SG, Parent JM (2010) Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37:267–274

    Article  PubMed  Google Scholar 

  • Kosugi I, Shinmura Y, Kawasaki H, Arai Y, Li RY, Baba S, Tsutsui Y (2000) Cytomegalovirus infection of the central nervous system stem cells from mouse embryo: a model for developmental brain disorders induced by cytomegalovirus. Lab Invest 80:1373–1383

    Article  PubMed  CAS  Google Scholar 

  • Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR (1997) Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278:1630–1632

    Article  PubMed  CAS  Google Scholar 

  • Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

    Article  PubMed  CAS  Google Scholar 

  • Lois C, Alvarez-Buylla A (1993) Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A 90:2074–2077

    Article  PubMed  CAS  Google Scholar 

  • Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  PubMed  CAS  Google Scholar 

  • Mishra MK, Basu A (2008) Minocycline neuroprotects, reduces microglial activation, inhibits caspase 3 induction, and viral replication following Japanese encephalitis. J Neurochem 105:1582–1595

    Article  PubMed  CAS  Google Scholar 

  • Mishra MK, Koli P, Bhowmick S, Basu A (2007) Neuroprotection conferred by astrocytes is insufficient to protect animals from succumbing to Japanese encephalitis. Neurochem Int 50:764–773

    Article  PubMed  CAS  Google Scholar 

  • Mohamed Ariff I, Mitra A, Basu A (2012) Epigenetic regulation of self-renewal and fate determination in neural stem cells. J Neurosci Res 90:529–539

    Article  PubMed  CAS  Google Scholar 

  • Morrison SJ (2001) Neuronal differentiation: proneural genes inhibit gliogenesis. Curr Biol 11:R349–R351

    Article  PubMed  CAS  Google Scholar 

  • Mui AL (1999) The role of STATs in proliferation, differentiation, and apoptosis. Cell Mol Life Sci 55:1547–1558

    Article  PubMed  CAS  Google Scholar 

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N (1998) Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273:29864–29872

    Article  PubMed  CAS  Google Scholar 

  • Nakashima K, Takizawa T, Ochiai W, Yanagisawa M, Hisatsune T, Nakafuku M, Miyazono K, Kishimoto T, Kageyama R, Taga T (2001) BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci U S A 98:5868–5873

    Article  PubMed  CAS  Google Scholar 

  • Odeberg J, Wolmer N, Falci S, Westgren M, Seiger A, Soderberg-Naucler C (2006) Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. J Virol 80:8929–8939

    Article  PubMed  CAS  Google Scholar 

  • Otaegi G, Yusta-Boyo MJ, Vergano-Vera E, Mendez-Gomez HR, Carrera AC, Abad JL, Gonzalez M, de la Rosa EJ, Vicario-Abejon C, de Pablo F (2006) Modulation of the PI 3-kinase-Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells. J Cell Sci 119:2739–2748

    Article  PubMed  CAS  Google Scholar 

  • Peruzzi F, Gordon J, Darbinian N, Amini S (2002) Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway. J Neurovirol 8(Suppl 2):91–96

    Article  PubMed  CAS  Google Scholar 

  • Rajan P, McKay RD (1998) Multiple routes to astrocytic differentiation in the CNS. J Neurosci 18:3620–3629

    PubMed  CAS  Google Scholar 

  • Romanko MJ, Rola R, Fike JR, Szele FG, Dizon ML, Felling RJ, Brazel CY, Levison SW (2004) Roles of the mammalian subventricular zone in cell replacement after brain injury. Prog Neurobiol 74:77–99

    Article  PubMed  Google Scholar 

  • Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376

    Article  PubMed  CAS  Google Scholar 

  • Swarup V, Das S, Ghosh S, Basu A (2007) Tumor necrosis factor receptor-1-induced neuronal death by TRADD contributes to the pathogenesis of Japanese encephalitis. J Neurochem 103:771–783

    Article  PubMed  CAS  Google Scholar 

  • Vrati S, Agarwal V, Malik P, Wani SA, Saini M (1999) Molecular characterization of an Indian isolate of Japanese encephalitis virus that shows an extended lag phase during growth. J Gen Virol 80(Pt 7):1665–1671

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grant awarded to AB from the Department of Biotechnology, Award # BT/PR8682/Med/14/1273/2007. A.B. is a recipient of the National Bioscience Award for Career Development-2010 from Department of Biotechnology. A part of this work was presented at 19th Biennial Meeting of the International Society for Developmental Neuroscience, 11–14 January 2012, Mumbai, India. Authors acknowledged excellent technical help from Kanhaiya Lal Kumawat and Kiran Kundu for plaque formation assay and immuno florescence staining respectively.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. National Brain Research Centre, Manesar, Haryana, 122051, India

    Iqbal Mohamed Ariff, Menaka C. Thounaojam, Sulagna Das & Anirban Basu

  2. Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, CT, 06032-3105, USA

    Sulagna Das

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  1. Iqbal Mohamed Ariff
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  2. Menaka C. Thounaojam
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  3. Sulagna Das
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  4. Anirban Basu
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Correspondence to Anirban Basu.

Additional information

Iqbal Mohamed Ariff and Menaka Chanu Thounaojam contributed equally as first authors.

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Ariff, I.M., Thounaojam, M.C., Das, S. et al. Japanese Encephalitis Virus Infection Alters Both Neuronal and Astrocytic Differentiation of Neural Stem/Progenitor Cells. J Neuroimmune Pharmacol 8, 664–676 (2013). https://doi.org/10.1007/s11481-013-9455-7

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