Understanding Enterovirus D68-Induced Neurologic Disease: A Basic Science Review

Abstract

In 2014, the United States (US) experienced an unprecedented epidemic of enterovirus D68 (EV-D68)-induced respiratory disease that was temporally associated with the emergence of acute flaccid myelitis (AFM), a paralytic disease occurring predominantly in children, that has a striking resemblance to poliomyelitis. Although a definitive causal link between EV-D68 infection and AFM has not been unequivocally established, rapidly accumulating clinical, immunological, and epidemiological evidence points to EV-D68 as the major causative agent of recent seasonal childhood AFM outbreaks in the US. This review summarizes evidence, gained from in vivo and in vitro models of EV-D68-induced disease, which demonstrates that contemporary EV-D68 strains isolated during and since the 2014 outbreak differ from historical EV-D68 in several factors influencing neurovirulence, including their genomic sequence, their receptor utilization, their ability to infect neurons, and their neuropathogenicity in mice. These findings provide biological plausibility that EV-D68 is a causal agent of AFM and provide important experimental models for studies of pathogenesis and treatment that are likely to be difficult or impossible in humans.

COVID‐19: A Global Threat to the Nervous System

“…[37][38][39] In the case of EV-D68-associated AFM, nasopharyngeal and throat swabs are frequently positive for virus by RT-PCR when obtained early after disease onset, yet, CSF RT-PCR tests are only positive in a small minority (<3%) of cases. 40 The sensitivity of SARS-CoV-2 RT-PCR in properly performed nasopharyngeal swabs for detection of acute COVID-19 is high, but data are currently too limited to evaluate sensitivity of this technique in CSF in patients with neurological disease.…”

Evolution, geographic spreading, and demographic distribution of Enterovirus D68

“…Enterovirus D68 (EV-D68) has caused worldwide outbreaks of serious respiratory and neurological disease in 2014 and thereafter. In particular, EV-D68 infection has been associated with acute flaccid myelitis (AFM) (Hixon et al, 2019). EV-D68 was first isolated in 1962, (Schieble et al, 1967) but rarely reported until the recent outbreaks (Centers for Disease Control and Pre- * Correspondence to:…”

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

“…Furthermore, ICAM-5 was not detected in neonatal mouse spinal cords where EV-D68 is preferentially found (Hixon et al, 2019b). It is possible that a homolog to ICAM-5 is the true neuronal-specific receptor for EV-D68 (Hixon et al, 2019b).…”

“…Although this receptor is abundantly expressed in neurons (Gahmberg et al, 2008) and shows promise for neuronal-specific tropism of neurotropic enteroviruses, the pattern of EV-D68 infection in brain slice models and microfluidic chamber motor neuron cultures does not correspond to the distribution or expression of ICAM-5 (Hixon et al, 2019a). In fact, ICAM-5 expression in human iPSC-derived motor neuron-like cells was observed within the soma and dendrites while EV-D68 viral particles were observed on the axon terminals (Hixon et al, 2019b). Furthermore, ICAM-5 was not detected in neonatal mouse spinal cords where EV-D68 is preferentially found (Hixon et al, 2019b).…”

“…In fact, ICAM-5 expression in human iPSC-derived motor neuron-like cells was observed within the soma and dendrites while EV-D68 viral particles were observed on the axon terminals (Hixon et al, 2019b). Furthermore, ICAM-5 was not detected in neonatal mouse spinal cords where EV-D68 is preferentially found (Hixon et al, 2019b). It is possible that a homolog to ICAM-5 is the true neuronal-specific receptor for EV-D68 (Hixon et al, 2019b).…”