Sialic acid-dependent cell entry of human enterovirus D68

Abstract

Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the ‘canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.

Enterovirus D68 receptor requirements unveiled by haploid genetics

“…Using knockout cell lines and gene reconstitution, we have shown that EV-D68 can use both α2,6-and α2,3-linked Sia as a receptor to infect cells. This finding extends recent observations that both α2,6-and α2,3-linked Sia-containing trisaccharides can bind to the EV-D68 capsid and initiate virion uncoating in vitro (26). The observation that EV-D68 can use not only α2,6-linked Sia as a receptor but also α2,3-linked Sia, which resides mainly in the lower respiratory tract, may provide an explanation for its ability to cause severe lower respiratory tract infections.…”

“…4 and Tables S1 and S2). Although residues that differed between Siadependent and -independent strains in clade A show little overlap with those that were altered in clade B, some of the changed residues on the viral surface are near the Sia-binding site (26) (Fig. 4).…”

“…S4). In EV-D68, binding of Sia induces virion destabilization and pocket factor release, which is the first step in the uncoating process (26). We identified several EV-D68 strains that can use a nonsialylated receptor while retaining a Sia-binding capacity, albeit with different affinities.…”

Cryo-EM of viruses and vaccine design

“…In their structural study of rhinovirus C, Liu et al (1) examine the shape of the canyon (14), a pocket at the base of the protruding spikes on the surface of the rhinovirus capsid. A similar location on the enterovirus D68, a related virus also associated with severe disease in children, had previously been shown to interact with sialylated cadherin-related family member 3 (CDHR3) (15). Whereas other rhinoviruses have flat plateaus and wide canyons in their capsid surface, the rhinovirus C surface canyons more closely resemble the surface canyons of enterovirus D68; a closer look at the canyons (Fig.…”

Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma

“…The canyon allows only limited access to these antibodies (22). In many EVs, a hydrophobic pocket within the VP1 jelly roll and situated underneath the canyon floor is occupied by a fatty-acid like molecule, or "pocket factor" (23,24), that regulates the conformational states of the virus during cell entry (25). Capsidbinding reagents that replace the pocket factor within VP1 are effective antiviral therapeutics against many EVs (26), but not RV-Cs (14).…”