Key result
In mice, overcoming both the neural transport barrier via muscle damage and the innate immune barrier via IFNAR knockout allowed 80% of the poliovirus population to access the brain and accelerated disease onset three-fold.
Absolute Event Rate: 80% vs 20%
p-value: p=<0.0001
Inefficient retrograde axonal transport and the type I interferon response act as substantial barriers limiting poliovirus trafficking from peripheral neurons to the central nervous system.
Preclinical mouse data preclude practice changes; leaves open whether these barriers limit human poliovirus neuroinvasion.
Poliovirus is an enteric virus that rarely invades the human central nervous system (CNS). To identify barriers limiting poliovirus spread from the periphery to CNS, we monitored trafficking of 10 marked viruses. After oral inoculation of susceptible mice, poliovirus was present in peripheral neurons, including vagus and sciatic nerves. To model viral trafficking in peripheral neurons, we intramuscularly injected mice with poliovirus, which follows a muscle-sciatic nerve-spinal cord-brain route. Only 20% of the poliovirus population successfully moved from muscle to brain, and three barriers limiting viral trafficking were identified. First, using light-sensitive viruses, we found limited viral replication in peripheral neurons. Second, retrograde axonal transport of poliovirus in peripheral neurons was inefficient; however, the efficiency was increased upon muscle damage, which also increased the transport efficiency of a non-viral neural tracer, wheat germ agglutinin. Third, using susceptible interferon (IFN) alpha/beta receptor knockout mice, we demonstrated that the IFN response limited viral movement from the periphery to the brain. Surprisingly, the retrograde axonal transport barrier was equivalent in strength to the IFN barrier. Illustrating the importance of barriers created by the IFN response and inefficient axonal transport, IFN alpha/beta receptor knockout mice with muscle damage permitted 80% of the viral population to access the brain, and succumbed to disease three times faster than mice with intact barriers. These results suggest that multiple separate barriers limit poliovirus trafficking from peripheral neurons to the CNS, possibly explaining the rare incidence of paralytic poliomyelitis. This study identifies inefficient axonal transport as a substantial barrier to poliovirus trafficking in peripheral neurons, which may limit CNS access for other viruses.
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Lancaster et al. (2010) studied Poliovirus infection. Muscle damage and IFNAR knockout vs. Intact barriers (wild-type mice without muscle damage) was evaluated on Proportion of viral population accessing the brain (p=<0.0001). In mice, overcoming both the neural transport barrier via muscle damage and the innate immune barrier via IFNAR knockout allowed 80% of the poliovirus population to access the brain and accelerated disease onset three-fold.
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