ICAM-1 functions as a functional receptor for encephalomyocarditis virus and reveals a compensatory interplay with ICAM-4.

Encephalomyocarditis virus (EMCV) is the most widespread zoonotic pathogen that causes piglet death. EMCV enters cells via caveolin-mediated endocytosis. However, the receptors required for EMCV entry into the cells are unknown. Here, we show that intercellular cell adhesion molecule-1 (ICAM-1) serves as a significant functional receptor during adsorption and entry. ICAM-1 binds directly to the EMCV viral proteins VP1 and VP2 with high affinity. Consistently, a soluble ICAM-1 fusion protein or anti-ICAM-1 blocking antibody impairs EMCV infection in susceptible human and mouse cells. Domain 1 of ICAM-1 is involved in the recognition of EMCV. ICAM-4 serves as a receptor in ICAM-1 knockout/knockdown mice and cell lines during EMCV infection. These findings suggest that ICAM-1 and ICAM-4 are entry receptors for EMCV and that targeting ICAM-1 D1 could be a potential strategy for the development of antivirals against EMCV.