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Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain. | LitMetric

Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain.

J Neuroinflammation

Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Ave, Pittsburgh, PA, 15282, USA.

Published: May 2016

AI Article Synopsis

  • The study investigates how anti-viral immune responses affect neural stem/progenitor cells (NSPCs) in neonates infected with the measles virus (MV), focusing on whether these effects are due to direct viral infection or the immune response itself.
  • Using a specific model where NSPCs remained uninfected, the researchers examined two types of mice: one with the MV entry receptor and one lacking the anti-viral cytokine IFNγ.
  • Results showed that NSPCs were reduced in mice lacking IFNγ, indicating that this cytokine plays a protective role against NSPC loss, but does not help protect young neurons during infection.

Article Abstract

Background: In the developing brain, self-renewing neural stem/progenitor cells (NSPC) give rise to neuronal and glial lineages. NSPC survival and differentiation can be altered by neurotropic viruses and by the anti-viral immune response. Several neurotropic viruses specifically target and infect NSPCs, in addition to inducing neuronal loss, which makes it difficult to distinguish between effects on NSPCs that are due to direct viral infection or due to the anti-viral immune response.

Methods: We have investigated the impact of anti-viral immunity on NSPCs in measles virus (MV)-infected neonates. A neuron-restricted viral infection model was used, where NSPCs remain uninfected. Thus, an anti-viral immune response was induced without the confounding issue of NSPC infection. Two-transgenic mouse lines were used: CD46+ mice express the human isoform of CD46, the MV entry receptor, under the control of the neuron-specific enolase promoter; CD46+/IFNγ-KO mice lack the key anti-viral cytokine IFNγ. Multi-color flow cytometry and Western Blot analysis were used to quantify effects on NSPC, neuronal, and glial cell number, and quantify effects on IFNγ-mediated signaling and cell markers, respectively.

Results: Flow cytometric analysis revealed that NSPCs were reduced in CD46+/IFNγ-KO mice at 3, 7, and 10 days post-infection (dpi), but were unaffected in CD46+ mice. Early neurons showed the greatest cell loss at 7 dpi in both genotypes, with no effect on mature neurons and glial cells. Thus, IFNγ protected against NSPC loss, but did not protect young neurons. Western Blot analyses on hippocampal explants showed reduced nestin expression in the absence of IFNγ, and reduced doublecortin and βIII-tubulin in both genotypes. Phosphorylation of STAT1 and STAT2 occurred independently of IFNγ in the hippocampus, albeit with distinct regulation of activation.

Conclusions: This is the first study to demonstrate bystander effects of anti-viral immunity on NSPC function. Our results show IFNγ protects the NSPC population during a neonatal viral CNS infection. Significant loss of NSPCs in CD46+/IFNγ-KO neonates suggests that the adaptive immune response is detrimental to NSPCs in the absence of IFNγ. These results reveal the importance and contribution of the anti-viral immune response to neuropathology and may be relevant to other neuroinflammatory conditions.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867982PMC
http://dx.doi.org/10.1186/s12974-016-0571-1DOI Listing

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