Critical roles for interferon-gamma producing immune cells during neonatal central nervous system infections (VIR1P.1005)

Abstract

Abstract Viral infections in the central nervous system (CNS) are associated with devastating neurological consequences, particularly in newborns. Despite mounting innate and adaptive immune responses, neonates are often unable to control viruses in the brain and suffer extensive neuronal loss, potentially due to deficits in anti-viral cytokines. To study the response of the neonatal immune system to viral CNS infections, our laboratory uses a transgenic mouse model (NSE-CD46) of neuron-restricted measles virus (MV) infection. NSE-CD46 mice express the human isoform of CD46, a MV receptor, under the control of the neuron specific enolase (NSE) promoter, allowing for infection only in CNS neurons. Adult NSE-CD46 mice clear MV from the CNS in an interferon gamma (IFNγ) and T-cell dependent manner. In contrast, neonatal NSE-CD46 mice succumb, with 100% mortality at 15 days post infection (dpi). Neonatal mice lacking IFNγ (CD46+/IFNγ-KO) succumb more rapidly than NSE-CD46+ neonates (100% mortality, 10 dpi) despite higher T-cell infiltration in the CNS. CD46+/RAG-2-KO neonates, which lack T- and B-cells, show reduced mortality in comparison to other CD46+ genotypes and have lower MV RNA. We hypothesize that MV control in CD46+/RAG2-KO neonates could be provided by IFNγ-producing natural killer (NK) cells. Current experiments aim to define the mechanism of viral control in the CD46+/RAG2-KO neonates. This work will answer critical questions about viral control in the neonatal CNS.