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A 2.8-Angstrom-Resolution Cryo-Electron Microscopy Structure of Human Parechovirus 3 in Complex with Fab from a
Aušra Domanska1,2, Justin W Flatt3,2, Joonas J J Jukonen3,2
1Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland ausra.domanska@helsinki.fi sarah.butcher@helsinki.fi.
Abstract:
Human parechovirus 3 (HPeV3) infection is associated with sepsis characterized by significant immune activation and subsequent tissue damage in neonates. Strategies to limit infection have been unsuccessful due to inadequate molecular diagnostic tools for early detection and the lack of a vaccine or specific antiviral therapy. Toward the latter, we present a 2.8-Å-resolution structure of HPeV3 in complex with fragments from a neutralizing human monoclonal antibody, AT12-015, using cryo-electron microscopy (cryo-EM) and image reconstruction. Modeling revealed that the epitope extends across neighboring asymmetric units with contributions from capsid proteins VP0, VP1, and VP3. Antibody decoration was found to block binding of HPeV3 to cultured cells. Additionally, at high resolution, it was possible to model a stretch of RNA inside the virion and, from this, identify the key features that drive and stabilize protein-RNA association during assembly.IMPORTANCE Human parechovirus 3 (HPeV3) is receiving increasing attention as a prevalent cause of sepsis-like symptoms in neonates, for which, despite the severity of disease, there are no effective treatments available. Structural and molecular insights into virus neutralization are urgently needed, especially as clinical cases are on the rise. Toward this goal, we present the first structure of HPeV3 in complex with fragments from a neutralizing monoclonal antibody. At high resolution, it was possible to precisely define the epitope that, when targeted, prevents virions from binding to cells. Such an atomic-level description is useful for understanding host-pathogen interactions and viral pathogenesis mechanisms and for finding potential cures for infection and disease.
Insights
Researchers visualized the structure of human parechovirus 3 (HPeV3) complexed with a neutralizing antibody. This structural insight is crucial for developing new treatments against HPeV3 infections in newborns.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Human parechovirus 3 (HPeV3) causes sepsis-like illness in neonates with severe immune activation and tissue damage.
- Current diagnostic tools and treatments for HPeV3 infection are insufficient, necessitating new therapeutic strategies.
Purpose of the Study:
- To determine the high-resolution structure of HPeV3 in complex with a neutralizing antibody fragment.
- To elucidate the molecular details of the antibody-virus interaction and identify the epitope for potential therapeutic targeting.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to obtain a 2.8-Å resolution structure.
- Image reconstruction and computational modeling were employed to analyze the complex and viral components.
Main Results:
- The structure revealed an epitope spanning multiple capsid proteins (VP0, VP1, VP3) across asymmetric units.
- Antibody binding effectively blocked HPeV3 attachment to cultured cells.
- High-resolution modeling also identified key features of protein-RNA interactions within the virion.
Conclusions:
- The atomic-level structural insights into HPeV3-antibody interaction provide a foundation for rational drug design.
- Understanding the epitope is critical for developing effective antiviral therapies and neutralizing antibodies against HPeV3.
- This work advances the understanding of viral pathogenesis and offers potential avenues for treating neonatal HPeV3 infections.
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