Neurotropic viruses present a huge challenge to human health, and are an increasing cause of morbidity and mortality worldwide. These viruses have greater impact compared to other pathogens, mainly because they target neuronal tissue, resulting in high rates of mortality. When patients survive, these viruses can leave severe and long lasting damage in the nervous system. It is often not feasible to develop experimental models of neural infection using in vivo models. Our data also suggest that the subcellular pathology of these viruses vary dramatically in animal models and continuous cell lines. Therefore current experimental models are unlikely to accurately represent neurotropic viral pathogenesis in humans.
We have therefore developed novel models of viral infection in neurons derived from human induced pluripotent and embryonic stem cell lines. We have optimised experimental conditions for infection to model both Hendra Virus (HeV) and West Nile Virus (WNV) infection within the human brain.
Our results show that both neural progenitors and differentiated neurons are susceptible to HeV infection. Ultrastructural rearrangements within the host cells are present in concert with a previously undescribed budding phenotype of HeV as it transmits from neuron to neuron. Using a chamber-well culture system and high-resolution fluorescence imaging, we have optimised growth of axons from neurons to further investigate the assembly of virus and determine the mechanism of neuron to neuron virus transmission within the brain.
This novel model is also being utilised as a platform with which to identify microRNA biomarkers of pre-symptomatic and neuronal virus infection. For example, we are expanding the application of this novel stem-cell model to analyse the biology of other neurotropic viruses. These experimental platforms will enable us to understand the viruses that threaten our health and support the development of new tools to combat viral-disease in the brain.