Role of enhanced receptor engagement in the evolution of a pandemic acute hemorrhagic conjunctivitis virus

Abstract

Acute hemorrhagic conjunctivitis (AHC) is a painful, contagious eye disease, with millions of cases in the last decades. Coxsackievirus A24 (CV-A24) was not originally associated with human disease, but in 1970 a pathogenic "variant" (CV-A24v) emerged, which is now the main cause of AHC. Initially, this variant circulated only in Southeast Asia, but it later spread worldwide, accounting for numerous AHC outbreaks and two pandemics. While both CV-A24 variant and nonvariant strains still circulate in humans, only variant strains cause AHC for reasons that are yet unknown. Since receptors are important determinants of viral tropism, we set out to map the CV-A24 receptor repertoire and establish whether changes in receptor preference have led to the increased pathogenicity and rapid spread of CV-A24v. Here, we identify ICAM-1 as an essential receptor for both AHC-causing and non-AHC strains. We provide a high-resolution cryo-EM structure of a virus-ICAM-1 complex, which revealed critical ICAM-1-binding residues. These data could help identify a possible conserved mode of receptor engagement among ICAM-1-binding enteroviruses and rhinoviruses. Moreover, we identify a single capsid substitution that has been adopted by all pandemic CV-A24v strains and we reveal that this adaptation enhances the capacity of CV-A24v to bind sialic acid. Our data elucidate the CV-A24v receptor repertoire and point to a role of enhanced receptor engagement in the adaptation to the eye, possibly enabling pandemic spread.

Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B

“…However, their differential roles remain undetermined. To date, several host receptors have been identified to facilitate the entry of enteroviruses, including CD155 (PVR) for poliovirus, intercellular adhesion molecule-1 (ICAM-1) for CV-A21 and CV-A24, scavenger receptor B2 (SCARB2) and P-selectin glycoprotein ligand-1 (PSGL-1) for EV-A71, and KREMEN1 for some of the group A enteroviruses (Abzug, 2014;Baggen et al, 2018;Mendelsohn et al, 1989;Nishimura et al, 2009;Staring et al, 2018;Tuthill et al, 2010;Xiao et al, 2001;Yamayoshi et al, 2009). For EV-B, CD55 has previously been reported as the receptor for CV-B1, -B3, -B5 and several other echovirus serotypes.…”

“…This binding triggers the release of ''pocket factor,'' which is hypothesized to be a lipid accommodated within a pocket below the canyon to stabilize the virion structure, and subsequently induces conformational changes in the viral particle (Bergelson and Coyne, 2013;Rossmann et al, 2002). The general con-cepts for enterovirus entry have previously been established using cryo-electron microscopy (cryo-EM) structures of several enteroviruses in complexes with their receptors at moderate resolutions, including poliovirus, CV-B3, CV-A21, and CV-A24 (Baggen et al, 2018;Bubeck et al, 2005;He et al, 2001;Organtini et al, 2014;Strauss et al, 2015;Xiao et al, 2005;Zhang et al, 2008). However, structural information of enterovirus-receptor complexes at atomic resolution and the mechanism of ''pocket factor'' release are missing, which would provide a much more accurate and systematic insight into the process of enterovirus entry.…”

Coxsackievirus A24 Variant Associated with Acute Haemorrhagic Conjunctivitis Cases, French Guiana, 2017

“…It has a marked ocular tropism due to the use of sialic acid as the cellular receptor [14]. Since the emergence of the EH24 strain, the ocular tropism of CV-A24v strains seems to have been increased by an amino acid substitution within the sialic acid-binding region of the capsid [15]. This substitution led to a tyrosine at VP1 position 250 and was recently found to enhance the ability of the virus to bind sialic acid [15].…”

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses

“…The terminal α2-6Neu5Ac is also rich in mucin-type O-glycans in tear films that could facilitate the spread of CVA24v [90]. While the emergence of pandemic EV70 in 1971 after its first recognition in 1969 and the second pandemic in 1980 are still mysteries, two pandemics caused by CVA24v in 1985 after the emergence of CVA24v/1970 causing an AHC outbreak and in 2002 have recently been investigated [98]. Both nonvariant and variant CVA24 viruses use ICAM-1 as an essential receptor, but only infection of the AHC-causing CVA24 variants into HCE cells significantly depends on a sialylated cell surface.…”

“…CVA24v/1970 virus causing AHC is still unknown, that enhanced Sia-binding engagement by a change of Phe250 to Tyr250 in VP1 contributed to the CVA24v/1970 ! CVA24v/1985 pandemic, and that the change responsible for the emergence of the CVA24v/2002 pandemic is still unknown [98].…”