# Molecular mechanisms of receptor recognition and antibody neutralization of coxsackievirus A6

## TL;DR

This study reveals how coxsackievirus A6 enters cells using two receptors and identifies antibodies that could lead to new treatments.

## Contribution

The study identifies a two-receptor mechanism for CVA6 entry and discovers new protective antibodies targeting a novel antigenic site.

## Key findings

- HSPG mediates viral attachment, while KRM1 induces uncoating in CVA6 entry.
- Two protective antibodies (1F4 and 3H7) block KRM1 binding and function post-attachment.
- CVA6 clinical strain HeB primarily exists as mature virions, confirmed via cryo-EM.

## Abstract

Coxsackievirus A6 (CVA6), a major cause of hand, foot, and mouth disease, lacks approved vaccines or drugs. KRM1 is its only known receptor, but its precise role remains unclear. This study investigates CVA6’s entry mechanism and antibody neutralization. Cryo-EM shows CVA6 clinical strain HeB primarily exists as mature virions. KRM1 binding within the canyon triggers conversion to uncoating intermediate, defining KRM1 as an uncoating receptor for CVA6. However, KRM1 knockout reduces CVA6 infectivity without affecting attachment. Conversely, disrupting heparan sulfate proteoglycan (HSPG) impairs both viral attachment and infectivity, and CVA6 virions bind heparin directly. These results support a two-receptor entry model for CVA6: HSPG mediates viral attachment, while KRM1 induces uncoating. Additionally, we develop two CVA6-specific protective antibodies (1F4 and 3H7), targeting a new antigenic site near the three-fold axis of the viral capsid. These antibodies sterically block KRM1 binding and function post-attachment, consistent with KRM1’s role. The findings elucidate CVA6 entry and offer a basis for antibody interventions.

This study defines a two-receptor entry mechanism for coxsackievirus A6: heparan sulfate for initial attachment and KRM1 for uncoating. Protective antibodies that block KRM1 binding were identified, offering a path for therapeutic development.