A large number of DNA and RNA viruses are neurotropic and can cause a variety of neurological disorders. The outcome of neurotropic viral infection depends on the virus and the infected neurons. In neurons, many viruses undergo a switch to a persistent infection which is often accompanied by a drastic reduction in production of cell-free viruses. However, despite reduction of extracellular viruses, many neurotropic viruses can disseminate within the CNS efficiently suggesting that these viruses may use novel ways of cell-to-cell transmission among neurons. The overall goal of this application is to identify the neuronal cell suppressor factor that restricts virus production and to elucidate how neurotropic viruses circumvent the neuron-specific restriction and spread within the CNS. In the proposed studies, a combination of neuronal cell culture systems and a transgenic mouse model will be used to compare the outcome of neuronal infection caused by two neurotropic viruses, namely, lymphocytic choriomeningitis virus (LCMV) and measles virus (MV).
Two specific aims are proposed to test the hypothesis that 1) neurons employ specific strategies to limit virus production and 2) neurotropic viruses can spread within the CNS by interneuronal transmission of viral particles that lack envelope components. While mice are natural hosts for LCMV, and neuronal infection by this virus is well-established, naturally occurring MV infections are restricted to humans due to the absence of the viral receptor in non-human cells. To facilitate studies of MV infection in vivo, transgenic mice carrying the gene of human MV receptor, CD46, controlled by the neuron-specific promoter to allow expression of the CD46 receptor in neurons have been established. Data are presented to show that cultured primary neurons from the transgenic embryos support MV infection and replication. Furthermore, when newborn transgenic mice were infected with MV, infection of MV was restricted to neurons. The infected transgenic mice also developed severe clinical signs. These transgenic mice will therefore facilitate both the in vitro and in vivo studies of MV infection proposed in this application. The results from the studies proposed will ultimately be used to determine how persistent viral infections evolve to induce CNS disease. By elucidating the state of the virus during a persistent infection and its mechanism of interneuronal spread, it is hoped that therapies can be developed to interfere with these processes and thus ameliorate the neurologic disorders induced by these viruses.
| Young, V A; Rall, G F (2009) Making it to the synapse: measles virus spread in and among neurons. Curr Top Microbiol Immunol 330:3-30 |
| Rose, R Wesley; Vorobyeva, Anna G; Skipworth, Jason D et al. (2007) Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J Neuroimmunol 192:145-56 |
| Makhortova, Nina R; Askovich, Peter; Patterson, Catherine E et al. (2007) Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology 362:235-44 |
