# Enterovirus D68 receptor usage: from static attachment to dynamic entry

## TL;DR

This paper reviews how Enterovirus D68 interacts with host cell receptors, explaining its ability to cause severe respiratory disease and neurological complications.

## Contribution

The paper highlights the discovery of MFSD6 as a broad-spectrum entry receptor for EV-D68, expanding understanding of its receptor versatility.

## Key findings

- α2,6-linked sialic acid acts as an attachment factor and uncoating trigger for historical EV-D68 strains.
- ICAM-5 is a neuron-specific receptor that explains EV-D68's neurotropism in AFM.
- MFSD6 is an essential entry receptor for a wide range of EV-D68 strains in respiratory and neuronal cells.

## Abstract

Enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen of notable clinical concern due to its association with severe respiratory disease and the paralytic complication acute flaccid myelitis (AFM). Viral tropism and pathogenesis are critically dictated by interactions with host cell receptors. Our understanding of this process has evolved from a simple model of sialic acid dependence to a dynamic paradigm involving a repertoire of attachment factors and proteinaceous entry receptors. This review synthesizes the evolving landscape of EV-D68 receptor usage. We detail the well-established role of α2,6-linked sialic acid as an attachment factor and uncoating trigger for historical strains. We further discuss the discovery of intracellular adhesion molecule-5 (ICAM-5) as a neuron-specific receptor that provides a molecular explanation for neurotropism in AFM. A pivotal recent advance is the identification of major facilitator superfamily domain-containing 6 (MFSD6) as an essential entry receptor for a broad range of EV-D68 strains in both respiratory and neuronal cells. We explore the implications of this receptor versatility, whereby the virus can switch between or co-opt sialic acid, ICAM-5, and MFSD6, a plasticity that influences tissue tropism and viral evolution. Finally, we highlight how these mechanistic insights, particularly the characterization of the MFSD6 interface, are paving the way for novel therapeutic strategies, such as engineered decoy receptors, and outline key future directions in the field.