Structural Studies of Human Enteroviruses
Enterovirus (EV), a genus within the Picornaviridae family, contains icosahedral positive-stranded RNA viruses linked to different human and mammalian diseases with a variety of symptoms ranging from the common cold to central nervous system infection. An important member within this genus is EV-D68. Unlike many enteroviruses that use the gastrointestinal tract as the transmission and propagation route, EV-D68 infects the respiratory tract and causes respiratory illness, especially in children. Severe infections of EV-D68 also lead to acute flaccid myelitis (AFM), a polio-like neurological disease. Especially in recent years, EV-D68 has been on a global upswing. However, no antiviral interventions against EV-D68 infection have been developed to date. Antibodies neutralizing EV-D68 have significant vaccine and therapeutic potentials. Here, the structures of the immune complex between EV-D68 and the Fab molecules of EV-D68 human monoclonal antibodies have been reconstructed using cryo-electron microscopy (cryo-EM). These structures show two Fab binding loci on the virion surface as well as the essential amino acids involved in binding. In addition to antibodies, a drug candidate against EV-D68 has been investigated in this work as an antiviral strategy. It is likely that this drug blocks viral entry through binding in the hydrophobic pocket underneath the viral protein 1, the largest structural protein of EV-D68. Furthermore, the morphogenesis of EV-D94, another causative virus of polio-like disease, which is closely related to EV-D68 with 85% sequence identity, has been investigated using cryo-EM. Compared to EV-D68, the shape of the canyon and the loops containing the immunogenic recognition sites are different in EV-D94. The structures of each of the three stages of EV-D94 particles (the full native virion, the uncoating intermediate, and the empty virion) were identified and delineate the viral uncoating process. These findings reveal useful knowledge and new insights to develop treatments against human EVs.
- Doctor of Philosophy
- Biological Sciences
- West Lafayette