Encephalomyelitis is one of the leading causes of morbidity and mortality associated with infections caused by viruses such as alphaviruses. The clinically important alphaviruses that can infect humans and animals comprise Sindbis virus, Venezuelan Equine Encephalitis virus, Eastern Equine Encephalitis virus, Western Equine Encephalitis virus, Ross River virus, Chikungunya virus and O’nyong-nyong virus [1]. Studies using Semliki Forest virus (SFV), a prototypical alphavirus, have shown that susceptibility to viral infections is age-dependent, and host maturation is associated with less severe encephalitis, with SFV strain A7(74) being lethal in young mice, but not in adult mice [2].
The innate immune system plays a critical protective role against viral infection. Using cultures of primary mouse embryonic neurons, we showed that there is a significant increase in virus replication in immature neurons compared to mature neurons, indicating that mature neurons can restrict the virus replication more efficiently. This differential susceptibility to SFV infection of immature neurons does not change following IFNβ pre-treatment. Furthermore, we found that IFNβ is not produced by immature neurons upon SFV infection, whereas mature neurons produce IFNβ and have higher expression levels of IFN-stimulated genes as well as overall increased production of cytokines and chemokines. We used RNA sequencing to further elucidate the mechanisms of maturation-dependent resistance of neurons to alphavirus infection.
This study provides invaluable insight into innate immune signalling pathways and host defence mechanisms of neuroprotection in adult neurons. It also has the potential to identify putative targets that might confer resistance to viral infection of developing neurons.