ICAM-1 is a cellular receptor for encephalomyocarditis virus

This study identifies intercellular adhesion molecule 1 (ICAM-1) and ICAM-4 as critical receptors for encephalomyocarditis virus (EMCV), elucidating the molecular basis of its broad host tropism and pathogenicity. By analyzing viral entry mechanisms across diverse cell lines and animal models, the research reveals that ICAM-1 directly interacts with EMCV capsid proteins VP1 and VP2 through its amino-terminal D1 domain, mediating viral attachment and internalization. Notably, ICAM-1's LFA-1-binding region facilitates this interaction, while structural mutations in VP1 and VP2 disrupt receptor binding, underscoring the specificity of this recognition. In the absence of ICAM-1, the study demonstrates a compensatory role for ICAM-4, which upregulates in knockout cells and similarly binds VP1/VP2 to sustain viral infection. This redundancy in receptor usage explains EMCV's ability to infect multiple species and tissues, including non-susceptible insect cells when ICAM-1 is artificially expressed. The findings also highlight the importance of the ICAM family in viral pathogenesis, offering insights into potential therapeutic targets that block receptor-ligand interactions to combat EMCV and related viruses.