Neuroinvasion by Theiloviruses

Theiler’s virus (or TMEV) is a murine neurotropic virus belonging to the picornavirus family. The intestinal infection is common in wild mice, but the nervous system infection is a rare event occurring in approximately 1 out of 2000 cases. The mechanisms that allow Theiler’s virus to reach the central nervous system (CNS) are not known. The first part of this work is thus dedicated to the study of the mechanisms leading to neuroinvasion by TMEV. On this purpose, we used a recently described TMEV strain named NIHE. We observed that this strain reproducibly reached the CNS after intraperitoneal administration or after administration in the footpad (FP). In the latter case, integrity of the sciatic nerve appeared to be essential for the progression of the virus to the CNS, suggesting that it might be transported along this nerve to reach the spinal cord. We showed that the type I interferon response has surprisingly little impact on neuroinvasion after footpad inoculation of the virus, whereas it strongly restricts neuroinvasion after IP inoculation. In the second part of this work, we wanted to decipher the mode of transport of the virus in neurons and to study the cell-to-cell transfer mechanisms. A non-lytic exit of the cell was demonstrated for some non-enveloped viruses and suggested for TMEV. Here, we describe the generation of a tool that is particularly useful for the purpose of our study: trans-encapsidated replicons. These replicon particles are limited to a single infection cycle, and might help to elucidate the limiting factors in the cell-to-cell transfer process and to unravel the state of the virus during axonal transport. We also present the use of particles in different models. Up to now, no propagation of such replicons could be evidenced, which means that either the production of complete viral particles is required for the cell-to-cell transfer of the virus, even in a non lytic process, or that experimental conditions did not allow the observation of such non-lytic transfer (cell types, in vitro conditions, sensitivity of the analysis methods, etc).(MED - Sciences médicales) -- UCL, 201