A collaborative effort to compare dissemination of three viruses
This study was based upon previous work from our lab showing that host barriers restrict poliovirus dissemination in mice. Specifically, poliovirus dissemination to the central nervous system was limited by inefficient transport in neurons and by type I interferon responses (Kuss et al., PLoS Path, 2008, 4:e1000082 and Lancaster et al., PLoS Path, 2010, 6:e1000791). These discoveries were made possible by using a pool of ten genetically tagged polioviruses to follow viral population diversity during dissemination from the injection site in the leg, through the sciatic nerve, up the spinal cord, and to the brain. We wondered whether other neurotropic viruses encounter these same host barriers. To test this, we compared dissemination of genetically tagged pools of poliovirus, yellow fever virus, and reovirus. For this study, we made nine tagged reoviruses in collaboration with Terry Dermody’s lab and we used a pool of six tagged yellow fever viruses (Erickson et al., J Virol, 2013, 87:12392-7). We found that these three viruses each disseminate to the brain through different pathways.
One of the main challenges for this study was to create genetically tagged reoviruses. Before 2007, targeted mutagenesis of the reovirus genome was impossible due to lack of an infectious clone. However, the Dermody lab developed a reverse genetic system in spite of the challenges conferred by a double-stranded RNA genome with ten segments (Kobayashi et al., Cell Host Microbe, 2007, 1:147-57). Using this system, we incorporated mutations into the plasmid encoding the M1 genome segment (see Fig. 1), sent the DNA to Vanderbilt, and Mine Ikizler in the Dermody lab rescued the viruses and sent them to us. Lauren Luethy then used these viruses to compare dissemination of reovirus, yellow fever virus, and poliovirus in mice. Therefore, collaboration was key for this study!
Our biggest surprise was that neural dissemination of poliovirus and reovirus occurred through distinct mechanisms. Both viruses entered the sciatic nerve, but retrograde trafficking of reovirus was far less efficient than poliovirus. Furthermore, muscle damage dramatically enhanced retrograde axonal transport of poliovirus, but had no effect on reovirus. These results suggest that in spite of similar trajectories to the spinal cord, poliovirus and reovirus use fundamentally different transport mechanisms. Future work may reveal the specific details of these different transport pathways.
Notebook page showing design of silent point mutation markers in the M1 segment of the reovirus genome.
About the authors
Pictured left: Lauren Luethy, photographed at her thesis defense party. Lauren was a graduate student in the Department of Microbiology at the University of Texas Southwestern Medical Center. She is now a Press Editorial Acquisitions Specialist at the American Society for Microbiology in Washington, D.C.
Pictured right: Julie Pfeiffer and Terry Dermody, photographed at a Predators-Red Wings hockey game after a seminar visit in Nashville (the Red Wings won). Julie Pfeiffer is an Associate Professor of Microbiology at the University of Texas Southwestern Medical Center and Terry Dermody is the Dorothy Overall Wells Professor of Pediatrics and Microbiology & Immunology, Director of the Division of Infectious Diseases, and Director of the Elizabeth B. Lamb Center for Pediatric Research at the Vanderbilt University School of Medicine.
About the research
Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system
Lauren N. Luethy, Andrea K. Erickson, Palmy R. Jesudhasan, Mine Ikizler, Terence S. Dermody, Julie K. Pfeiffer
Virology, Volume 487, January 2016, Pages 1–10