Enterovirus D68 (EV-D68) is a virus that normally causes disease in children. While this virus typically causes a respiratory infection, in 2014, a large outbreak of the virus was associated with patients that had paralysis of the arms or legs. Even though the virus was discovered in 1962, little was known about the life cycle of the virus or its ability to cause disease. An animal model of disease was needed to understand how the virus causes disease and to develop antiviral compounds to target the virus life cycle. We adapted the virus by serial-passage in lung tissues from mice deficient in interferon receptors. Using the adapted virus, we established a model of respiratory disease where the virus was able to replicate and cause moderate damage to the lung tissue. We created a separate model of disease where the virus caused paralysis and mortality in infected mice, similar to symptoms seen in infected children. Lastly, we evaluated several antiviral compounds to determine if they were able to protect the mice from virus replication and mortality. Guanidine was able to reduce the amount of virus in each tissue as well as protect mice from paralysis and mortality. In addition, human intravenous immunoglobulin (hIVIG), a mixture of pooled antibodies from human donors, did not reduce the amount of virus in the lungs, but did protect mice from paralysis and mortality.

Enterovirus D68 (EV-D68) virus has become more prevalent over the last 15 to 20 years. EV-D68 attacks the respiratory system and can cause severe disease in individuals who have underlying respiratory problems. There have also been reports of individuals with EV-D68 showing signs of neurological system problems and acute flaccid paralysis. Because of the increase in patients with EV-D68 and also the potential for neurological disease, an animal model is needed to study the disease and to evaluate experimental therapies for EV-D68 infection. To develop the animal model, 4-week old AG129 mice that lack alpha and beta interferon receptors, making them immunosuppressed, were used. The mice were infected with EV-D68 by the intranasal route to allow infection of the lungs. On day-3 post-infection the mice were euthanized and lungs were removed and homogenized for collection of virus. The newly collected virus was then used to infect another set of mice. This procedure was repeated 30 times. As passage number increased so did the amount of virus that was collected from the lungs of mice. The virus titer increased 320-fold between mouse passage 0 to 30. At the end of the thirtieth passage, multiple tissues (lungs, liver, kidney, spleen, blood, brain, spinal cord and leg muscle) were collected from infected mice over several days and titered to demonstrate how quickly the virus spread to various tissues within the mouse. The virus replicated most rapidly in the lungs and remained in the lungs longer than the other tissues evaluated. However, large quantities of virus were found in all tissues evaluated. Finally, several experimental antiviral compounds were evaluated: rupintrivir, pleconaril, ribavirin, enviroxime and guanidine, all of which showed therapeutic potential in cell culture. In the animal model rupintrivir, pleconaril, ribavirin and enviroxime did not show any therapeutic effect. Only guanidine reduced the amount of virus that was found in the lungs as well as in whole blood.

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