IFNγ protects neonatal neuronal precursor cells during measles virus infection of the brain (VIR1P.1007)

Abstract

Abstract In the developing brain, self-renewing neural stem/progenitor cells (NSPC) differentiate into neurons or glia. NSPC survival and differentiation can be altered by neurotropic viruses and by the anti-viral immune response. We hypothesize that interferon-gamma (IFNγ), a pro-inflammatory cytokine required for non-cytolytic clearance of many neurotropic viruses, alters NSPC proliferation and cell fate in measles virus (MV)-infected neonates. Two transgenic mouse lines were used: CD46+ express human CD46, a receptor for MV, under the neuron-specific enolase promoter, thereby restricting MV infection to mature neurons; CD46+/IFNγ-KO lack IFNγ. In our model, NSPCs are not infected, allowing us to evaluate the impact of solely the immune response on NSPCs. Flow cytometry and western blot were used to quantify effects on cell number and IFNγ-mediated signaling, respectively. Mice were mock- or MV-infected on postnatal day 2 and sacrificed 3, 7, and 10 days post-infection. Whole brain isolates were double-labeled with BrdU and markers for NSPCs (nestin), early neuronal lineage (CD24), and glial lineage (GFAP, O4). CD24+ cells showed the greatest cell loss at 7 dpi in both genotypes. NSPCs were reduced in CD46+/IFNγ-KO mice at 3 and 7 dpi, but unaffected in CD46+ mice. Thus, IFNγ may protect against NSPC, but not neuronal, loss. Current experiments aim to address the cell fate of NSPCs exposed to the antiviral immune response and define mechanisms of NSPC loss in CD46+/IFNγ-KO neonates.