Neural stem cell depletion and CNS developmental defects after enteroviral infection

Am J Pathol. 2012 Mar;180(3):1107-1120. doi: 10.1016/j.ajpath.2011.11.016. Epub 2011 Dec 31.


Coxsackieviruses are significant human pathogens causing myocarditis, meningitis, and encephalitis. We previously demonstrated the ability of coxsackievirus B3 (CVB3) to persist within the neonatal central nervous system (CNS) and to target neural stem cells. Given that CVB3 is a cytolytic virus and may therefore damage target cells, we characterized the potential reduction in neurogenesis within the developing brain and the subsequent developmental defects that occurred after the loss of these essential neural stem cells. Neonatal mice were inoculated with a recombinant CVB3 expressing eGFP (eGFP-CVB3), and alterations in neurogenesis and brain development were evaluated over time. We observed a reduction in proliferating cells in CNS neurogenic regions simultaneously with the presence of nestin(+) cells undergoing apoptosis. The size of the brain appeared smaller by histology, and a permanent decrease in brain wet weight was observed after eGFP-CVB3 infection. We also observed an inverse relationship between the amount of virus material and brain wet weight up to day 30 postinfection. In addition, signs of astrogliosis and a compaction of the cortical layers were observed at 90 days postinfection. Intriguingly, partial brain wet weight recovery was observed in mice treated with the antiviral drug ribavirin during the persistent stage of infection. Hence, long-term neurological sequelae might be expected after neonatal enteroviral infections, yet antiviral treatment initiated long after the end of acute infection might limit virus-mediated neuropathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antiviral Agents / pharmacology
  • Apoptosis / physiology
  • Astrocytes / virology
  • Brain / growth & development
  • Brain / virology
  • Cell Division
  • Cell Proliferation
  • Central Nervous System / growth & development
  • Central Nervous System / virology*
  • Coxsackievirus Infections / complications*
  • Enterovirus B, Human*
  • Green Fluorescent Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neural Stem Cells / virology*
  • Neurogenesis / physiology*
  • Organ Size
  • Recombinant Proteins
  • Viral Load


  • Antiviral Agents
  • Recombinant Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins