Abstract
Acute flaccid myelitis (AFM) is a rare but serious illness of the nervous system, specifically affecting the gray matter of the spinal cord, motor-controlling regions of the brain, and cranial nerves. Most cases of AFM are pathogen associated, typically with poliovirus and enterovirus infections, and occur in children under the age of 6 years. Enterovirus D68 (EV-D68) was first isolated from children with pneumonia in 1962, but an association with AFM was not observed until the 2014 outbreak. Organotypic mouse brain slice cultures generated from postnatal day 1 to 10 mice and adult ifnar knockout mice were used to determine if neurotropism of EV-D68 is shared among virus isolates. All isolates replicated in organotypic mouse brain slice cultures, and three isolates replicated in primary murine astrocyte cultures. All four EV-D68 isolates examined caused paralysis and death in adult ifnar knockout mice. In contrast, no viral disease was observed after intracranial inoculation of wild-type mice. Six of the seven EV-D68 isolates, including two from 1962 and four from the 2014 outbreak, replicated in induced human neurons, and all of the isolates replicated in induced human astrocytes. Furthermore, a putative viral receptor, sialic acid, is not required for neurotropism of EV-D68, as viruses replicated within neurons and astrocytes independent of binding to sialic acid. These observations demonstrate that EV-D68 is neurotropic independent of its genetic lineage and can infect both neurons and astrocytes and that neurotropism is not a recently acquired characteristic as has been suggested. Furthermore, the results show that in mice the innate immune response is critical for restricting EV-D68 disease.IMPORTANCE Since 2014, numerous outbreaks of childhood infections with enterovirus D68 (EV-D68) have occurred worldwide. Most infections are associated with flu-like symptoms, but paralysis may develop in young children. It has been suggested that infection only with recent viral isolates can cause paralysis. To address the hypothesis that EV-D68 has recently acquired neurotropism, murine organotypic brain slice cultures, induced human motor neurons and astrocytes, and mice lacking the alpha/beta interferon receptor were infected with multiple virus isolates. All EV-D68 isolates, from 1962 to the present, can infect neural cells, astrocytes, and neurons. Furthermore, our results show that sialic acid binding does not play a role in EV-D68 neuropathogenesis. The study of EV-D68 infection in organotypic brain slice cultures, induced motor neurons, and astrocytes will allow for the elucidation of the mechanism by which the virus infection causes disease.
Highlights
Acute flaccid myelitis (AFM) is a rare but serious illness of the nervous system, affecting the gray matter of the spinal cord, motor-controlling regions of the brain, and cranial nerves
Some children who were diagnosed with severe respiratory distress induced by enterovirus D68 (EV-D68) infection developed an acute flaccid myelitis (AFM) similar to that caused by poliovirus, a related enterovirus [2, 3, 6, 7, 10,11,12, 17]
The New York (NY), 947, and Rhyne isolates replicated in mouse embryonic fibroblast cell line (MEF), while all but the Rhyne isolate replicated in the N2A cultures (Fig. 1)
Summary
Acute flaccid myelitis (AFM) is a rare but serious illness of the nervous system, affecting the gray matter of the spinal cord, motor-controlling regions of the brain, and cranial nerves. To address the hypothesis that EV-D68 has recently acquired neurotropism, murine organotypic brain slice cultures, induced human motor neurons and astrocytes, and mice lacking the alpha/beta interferon receptor were infected with multiple virus isolates. 2018 [1,2,3,4,5,6,7,8,9,10, 12, 14,15,16] During these epidemics, some children who were diagnosed with severe respiratory distress induced by EV-D68 infection developed an acute flaccid myelitis (AFM) similar to that caused by poliovirus, a related enterovirus [2, 3, 6, 7, 10,11,12, 17]. EV-D68 is rarely shed in the feces of infected patients [27, 28], because infectivity is destroyed by the low pH of the stomach [25]
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