Influenza A virus infection of neurons and pathogenesis in the CNS
Riley Williams1,2, Christine Matullo1, Katelynn Milora1, Glenn Rall1
1Fox Chase Cancer Center; 2Drexel University College of Medicine, Philadelphia, Pennsylvania
Influenza A virus (IAV) is primarily known for infection of the respiratory tract, where it targets lung epithelial cells. Far less is understood about IAV infection of other cell types, especially those of the central nervous system (CNS). However, multiple neurotropic strains of IAV exist that can have severe neurological consequences, including encephalitis and meningitis, that can lead to death. Research aimed at uncovering the mechanisms by which IAV replicates and spreads within the CNS and how neurons respond to infection is therefore of increasing importance. We have shown that mouse primary neuron cultures, isolated from the embryonic hippocampus, are susceptible to infection by the PR8 and WSN strains of IAV. While PR8 has traditionally been considered non-neurotropic, we show that this virus efficiently replicates and spreads within neurons. WSN is considered to be neurotropic and was also capable of infecting primary neurons. Both PR8 and WSN viral RNA, mRNA, and protein are produced and accumulate, albeit with differing kinetics, throughout the course of infection before clearance. Interestingly, WSN appears to cause neuronal death ex vivo, although delayed compared to non-neuronal cells, while PR8 does not cause death. This suggests that the innate immune response to these two similar viruses is different in neurons. Current research is aimed at uncovering the basis for the differences in replication kinetics and the innate immune response following infection, and determining how these distinct outcomes impact neuropathogenesis in vivo. Understanding the differences between strains of IAV that are known to cause CNS disease and those that do not (to our knowledge), will be crucial as we consider the neuropathogenic potential of this major human pathogen.