Neuronal Dissemination Patterns of Three Distinct Viruses and Mechanisms Regulating Viral Retrograde Axonal Transport

Viruses from several distinct families can infect the central nervous system (CNS), but mechanisms and host factors that influence dissemination are not completely understood. I previously identified barriers that limit poliovirus and yellow fever virus 17D (YFV-17D) dissemination following peripheral injection of mice. To investigate how different viruses disseminate from peripheral tissue to the CNS, I intramuscularly injected mice with genetically marked pools of viruses and monitored dissemination along the sciatic nerve to the spinal cord and brain. Transport efficiency of each virus was compared in immune competent and immune deficient mice in the presence or absence of muscle damage, which was previously shown to enhance retrograde axonal transport of poliovirus in the sciatic nerve. I found that immune deficiency enhanced poliovirus and YFV-17D transport to the CNS. While muscle damage dramatically enhanced poliovirus dissemination it did not enhance YFV-17D dissemination, likely because YFV-17D entered the CNS through the blood. Like poliovirus, reovirus type 3 Dearing strain is transported through peripheral nerves to the CNS. Using genetically marked reoviruses, I found that young age and immune deficiency, but not muscle damage, enhanced reovirus transport to the CNS from peripheral tissues. Overall, my data suggest that these three viruses access the CNS through different routes and with different efficiencies. Though muscle damage enhances neuronal poliovirus dissemination, the mechanisms that regulate this are unclear. I tested dissemination of the marked viruses following intramuscular injection in the presence or absence of potential regulatory factors. Several growth factors, including brain-derived neurotrophic factor, were previously shown to enhance retrograde axonal transport. In conjunction with poliovirus injection, brain-derived neurotrophic factor or other growth factors were not observed to enhance viral dissemination. Microarray analysis of muscle samples was performed to compare host gene expression in damaged and non-damaged tissue. Several host transcripts had elevated transcript levels in damaged muscles, including tissue inhibitor of metalloproteinase-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1). The targets of TIMP regulation, matrix metalloproteinases (MMPs), were previously shown to stimulate retrograde axonal transport following damage to peripheral tissues. MCP-1 has also been suggested to enhance viral dissemination. Altering MCP-1 or MMP levels during poliovirus infection revealed no direct impact on poliovirus dissemination. Though mechanisms regulating viral dissemination following muscle damage remain unclear, the path is open for exploration.