Mapping Attenuation Determinants in Enterovirus-D68

• Main Authors: Ming Te Yeh, Sara Capponi, Adam Catching, Simone Bianco, Raul Andino
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: Viruses
• Subjects: enterovirus; enterovirus-D68; virulence determinant; mouse model; infectious clones; VP3
• Online Access: https://www.mdpi.com/1999-4915/12/8/867

Enterovirus (EV)-D68 has been associated with epidemics in the United Sates in 2014, 2016 and 2018. This study aims to identify potential viral virulence determinants. We found that neonatal type I interferon receptor knockout mice are susceptible to EV-D68 infection via intraperitoneal inoculation and were able to recapitulate the paralysis process observed in human disease. Among the EV-D68 strains tested, strain US/MO-14-18949 caused no observable disease in this mouse model, whereas the other strains caused paralysis and death. Sequence analysis revealed several conserved genetic changes among these virus strains: nucleotide positions 107 and 648 in the 5′-untranslated region (UTR); amino acid position 88 in VP3; 1, 148, 282 and 283 in VP1; 22 in 2A; 47 in 3A. A series of chimeric and point-mutated infectious clones were constructed to identify viral elements responsible for the distinct virulence. A single amino acid change from isoleucine to valine at position 88 in VP3 attenuated neurovirulence by reducing virus replication in the brain and spinal cord of infected mice.