Evaluating Treatment Efficacy in a Mouse Model of Enterovirus D68–Associated Paralytic Myelitis

Hixon, Alison M.; Clarke, Penny; Tyler, Kenneth L.

doi:10.1093/infdis/jix468

Cited by 83 publications

(94 citation statements)

References 44 publications

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“…injection of EV-D68 (IL/14-18952). The C56BL/6 mice had the rapid onset of limb paralysis that was identical to the paralysis onset and progression previously seen in Swiss Webster mice (data not shown) (17,18).…”

supporting

confidence: 76%

“…infection than following i.c. infection, dependent on the viral strain and the titer of the injected inoculum (17,18). These observations are in contrast to those with other neurotropic viruses, such as reovirus and West Nile virus, in which disease is more easily produced by direct CNS infection rather than peripheral infection (39,40).…”

Section: Discussionmentioning

confidence: 94%

“…Sectioning and staining of the entire cervical (triceps injected) or lumbar (hamstrings injected) spinal cord segments revealed that fluoro-ruby could be found in the spinal cord corresponding to the injected limb at the spinal cord level associated with the injected muscle as early as day postinfection (dpi) 1, although no viral antigen was detected in any mouse examined at this time point (data not shown). Previous mouse studies have shown that paralysis onset typically occurs on dpi 3 or 4 (17,18). Examination of the mice at 2 to 3 dpi, prior to the onset of paralysis, revealed that EV-D68 antigen could first be detected in neurons within regions of the cervical and lumbar spinal cord anterior horn regions also containing fluoro-ruby ( Fig.…”

mentioning

confidence: 82%

“…We previously developed a neonatal mouse model of EV-D68 infection that recapitulates features of AFM (17,18). In these mice, infection with contemporary circulating strains of EV-D68 by several routes of inoculation (intracerebral [i.c.…”

mentioning

confidence: 99%

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Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Hixon

Clarke²,

Tyler

2019

J Virol

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Enterovirus D68 (EV-D68) is an emerging virus that has been identified as a cause of recent outbreaks of acute flaccid myelitis (AFM), a poliomyelitis-like spinal cord syndrome that can result in permanent paralysis and disability. In experimental mouse models, EV-D68 spreads to, infects, and kills spinal motor neurons following infection by various routes of inoculation. The topography of virus-induced motor neuron loss correlates with the pattern of paralysis. The mechanism(s) by which EV-D68 spreads to target motor neurons remains unclear. We sought to determine the capacity of EV-D68 to spread by the neuronal route and to determine the role of known EV-D68 receptors, sialic acid and intracellular adhesion molecule 5 (ICAM-5), in neuronal infection. To do this, we utilized a microfluidic chamber culture system in which human induced pluripotent stem cell (iPSC) motor neuron cell bodies and axons can be compartmentalized for independent experimental manipulation. We found that EV-D68 can infect motor neurons via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies. Virus was not released from the axons via anterograde axonal transport after infection of the cell bodies. Prototypic strains of EV-D68 depended on sialic acid for axonal infection and transport, while contemporary circulating strains isolated during the 2014 EV-D68 outbreak did not. The pattern of infection did not correspond with the ICAM-5 distribution and expression in either human tissue, the mouse model, or the iPSC motor neurons. IMPORTANCE Enterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.

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supporting

confidence: 76%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 82%

mentioning

confidence: 99%

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Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Hixon

Clarke²,

Tyler

2019

J Virol

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“…EV-D68 causes infection and death in some reports of mouse infection models (38)(39)(40)(41). Thus, we evaluated the protective efficacy of A6-1 in 2-d-old suckling C57BL/6 mice.…”

Section: Animal Protectionmentioning

confidence: 99%

A Novel Neutralizing Antibody Specific to the DE Loop of VP1 Can Inhibit EV-D68 Infection in Mice

Zheng

Wang

et al. 2018

The Journal of Immunology

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Enterovirus D68 (EV-D68) belongs to the picornavirus family and was first isolated in CA, USA, in 1962. EV-D68 can cause severe cranial nerve system damage such as flaccid paralysis and acute respiratory diseases such as pneumonia. There are currently no efficient therapeutic methods or effective prophylactics. In this study, we isolated the mAb A6-1 from an EV-D68–infected rhesus macaque (Macaca mulatta) and found that the Ab provided effective protection in EV-D68 intranasally infected suckling mice. We observed that A6-1 bound to the DE loop of EV-D68 VP1 and interfered with the interaction between the EV-D68 virus and α2,6-linked sialic acids of the host cell. The production of A6-1 and its Ab properties present a bridging study for EV-D68 vaccine design and provide a tool for analyzing the process by which Abs can inhibit EV-D68 infection.

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Enterovirus D68–Associated Acute Flaccid Myelitis

Messacar

Tyler²

2019

JAMA

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Evaluating Treatment Efficacy in a Mouse Model of Enterovirus D68–Associated Paralytic Myelitis

Abstract: Results in this model of EV-D68-associated AFM provide a rational basis for selecting empirical therapy in humans and establish this model as a useful system for evaluating other potential therapies.

Cited by 83 publications

References 44 publications

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

A Novel Neutralizing Antibody Specific to the DE Loop of VP1 Can Inhibit EV-D68 Infection in Mice

Enterovirus D68–Associated Acute Flaccid Myelitis

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