Limited Trafficking of a Neurotropic Virus Through Inefficient Retrograde Axonal Transport and the Type I Interferon Response

Abstract

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) α/β 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 α/β 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.

Dynamic ubiquitination drives herpesvirus neuroinvasion

“…In the case of the latter, mechanical tissue disruption at the site of inoculation bypasses intrinsic protective barriers in the skin and increases retrograde transport in damaged axons as part of a peripheral nerve repair response (36,37). The concept that tissue trauma can increase the susceptibility of the nervous system to neurotropic viruses is best documented for poliovirus, which is rarely neuroinvasive except when provoked by tissue injury (38)(39)(40). The near impenetrability of the nervous system in healthy tissue indicates that effective intrinsic barriers to infection exist between peripheral tissues and the PNS.…”

Viruses in human central nervous system — invasion, transmission, and latency: a literature review

“…При этом разные вирусы имеют свою специфику. Так, ретроградный транспорт полиовируса в ЦНС будет неэффективным при повреждении мышцы в месте инфицирования [71]; при инфицировании PRV (псев-дорабивирус) паракринные сигналы поврежденной ткани блокируют нейральную инвазию [72,73].…”

Merging of viral concentration waves in retrograde viral transport in axons

“…Diffusivity can also be caused by cargo navigation around obstacles during motor-driven transport. Degradation of the virus as it travels from the axon terminal toward the neuron soma is accounted for by a first-order decay rate (such degradation is important, for example, in the case of the poliovirus [17]). Under these assumptions, retrograde transport of viruses in an axon is governed by the following equation:…”

“…Some viruses, such as the West Nile virus, can spread in both retrograde and anterograde directions [16]; however, most neurotropic viruses, such as the rabies virus, herpes virus, and polio virus enter the neuron via endocytosis at the presynaptic terminal of the axon and then utilize dynein motors in order to be trans-ported in the retrograde direction toward the neuron soma [17][18][19][20].…”