Enterovirus D68 molecular and cellular biology and pathogenesis

Abstract

In recent years, enterovirus D68 (EV-D68) has advanced from a rarely detected respiratory virus to a widespread pathogen responsible for increasing rates of severe respiratory illness and acute flaccid myelitis (AFM) in children worldwide. In this review, we discuss the accumulating data on the molecular features of EV-D68 and place these into the context of enterovirus biology in general. We highlight similarities and differences with other enteroviruses and genetic divergence from own historical prototype strains of EV-D68. These include changes in capsid antigens, host cell receptor usage, and viral RNA metabolism collectively leading to increased virulence. Furthermore, we discuss the impact of EV-D68 infection on the biology of its host cells, and how these changes are hypothesized to contribute to motor neuron toxicity in AFM. We highlight areas in need of further research, including the identification of its primary receptor and an understanding of the pathogenic cascade leading to motor neuron injury in AFM. Finally, we discuss the epidemiology of the EV-D68 and potential therapeutic approaches.

Global prevalence and case fatality rate of Enterovirus D68 infections, a systematic review and meta-analysis

“…A recent study on the use of fluoxetine in patients with AFM found that fluoxetine was well tolerated and safe. In addition, immune suppressive therapies have also been used by some centers to target the inflammatory response to infection [ 131 ]. It should be noted that recently much progress has been made in the development of the EV-D68 antivirals by targeting various viral proteins and host factors essential for viral replication [ 132 ].…”

Enterovirus D: A Small but Versatile Species

“…As a result, most antiviral research has targeted this virus. Several antiviral strategies have been proposed (reviewed in References [ 165 , 166 ]) such as capsid-binding compounds [ 145 , 167 , 168 , 169 , 170 , 171 ], viral proteases’ inhibitors [ 168 , 169 , 172 , 173 , 174 ], drugs targeting the non-structural proteins 2C [ 168 , 175 , 176 ], 3A [ 167 , 168 , 169 , 177 ], the viral polymerase 3D [ 167 , 169 , 178 , 179 ] and drugs blocking translation [ 180 ]. However, even the most favourable candidates did not obtain promising results in the mouse models [ 175 , 181 ].…”

Animal Models of Enterovirus D68 Infection and Disease

“…Phylogenetic analyses of contemporary versus prototype EV-D68 strains have revealed significant genetic viral evolution over time. Studies in vitro have characterized several functional impacts of these changes on host cell receptor usage and viral RNA metabolism that may contribute to expanded tissue tropism and increased virulence in vivo (reviewed in reference 3 ). Still, there are significant gaps in our understanding of EV-D68 pathogenesis in vivo , including knowledge of target cell types, mechanisms of systemic viral dissemination and tissue-specific infection, host innate and adaptive immune responses, and the relative contributions of both virus- and host-specific factors in disease progression and severity.…”