A neonatal mouse model of Enterovirus D68 infection induces both interstitial pneumonia and acute flaccid myelitis

Sun, Shiqi; Bian, Lianlian; Gao, Fan; Du, Ruixiao; Hu, Yalin; Fu, Ying Hui; Su, Yao; Wu, Xing; Mao, Qunying; Liang, Zhenglun

doi:10.1016/j.antiviral.2018.11.013

Cited by 39 publications

(42 citation statements)

References 39 publications

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“…Human AFM patients present with inflammation and the loss of motor neurons in the brain stem and spinal cord but do not show signs of generalized encephalitis (7,10). Consistent with this observation, studies with mouse models developed by several independent research groups have shown that infection by contemporary EV-D68 strains results in minimal replication within the brains of infected animals but robust replication in spinal cord and muscle tissue (17,41,42). In addition, motor pathways from the upper motor neurons of the brain to the lower motor neurons are anterograde connections.…”

Section: Discussionmentioning

confidence: 78%

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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Section: Discussionmentioning

confidence: 78%

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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“…Ninety-six-well flat-bottom Nunc-Immuno plates, MaxiSorp surface (Thermo Fisher Scientific) were coated with TMEV antigen at 4 • C overnight. After blocking with 10% fetal bovine serum (FBS) and 0.2% Tween 20 in PBS, 2 7 -or 2 11 -fold diluted serum samples were plated. Horseradish peroxidase (HRP)-conjugated anti-mouse IgG1 (Thermo Fisher Scientific), IgG2b (Thermo Fisher Scientific), IgG2c (SouthernBiotech, Birmingham, AL), or IgA (Thermo Fisher Scientific) was used to detect binding anti-TMEV isotype antibodies.…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation

et al. 2020

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Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression Omura et al. Microbiome in MS Viral Model and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM-and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.

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“…Neurotropism of enterovirus D68 is supported by neuronal cell culture studies, 31 and enterovirus D68 infection causes a clinical syndrome consistent with AFM in animal models. 32,33 These factors make direct neuronal infection a more plausible explanation for enterovirus D68-associated AFM than a parainfectious immune-mediated phenomenon. However, there remain many unanswered questions regarding the association between enterovirus D68 and AFM, including why only a small proportion of exposed individuals seem to develop neurological manifestations.…”

Section: Potential Etiological Factorsmentioning

confidence: 99%

Acute Flaccid Myelitis: A Clinical Review

Murphy

Pardo

2020

Semin Neurol

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Acute flaccid myelitis (AFM) is an emerging disorder primarily affecting children that is characterized by acute flaccid paralysis accompanied by abnormalities of the spinal cord gray matter on magnetic resonance imaging. In most cases, prodromal fever or respiratory symptoms occur, followed by acute-onset flaccid limb weakness. Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected. The clinical manifestations have been described as “polio-like,” due to striking similarities to cases of poliomyelitis. The primary site of injury in AFM is the anterior horn cells of the spinal cord, resulting in a motor neuronopathy. Seasonal peaks of cases have occurred in the United States every 2 years since 2012. However, AFM remains a rare disease, which can make it challenging for physicians to recognize and differentiate from other causes of acute flaccid paralysis such as Guillain–Barre syndrome, spinal cord stroke, and transverse myelitis. Epidemiological evidence suggests that AFM is linked to a viral etiology, with nonpolio enteroviruses (in particular enterovirus D68) demonstrating a plausible association. The epidemiology, possible etiological factors, clinical features, differential diagnosis, treatment, and outcomes of AFM are discussed in this review.

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A neonatal mouse model of Enterovirus D68 infection induces both interstitial pneumonia and acute flaccid myelitis

Cited by 39 publications

References 39 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

Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation

Acute Flaccid Myelitis: A Clinical Review

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