Research Spotlight: Learning More About the Structure of Viruses Used for Insecticides and Therapeutic Gene Delivery

Friederike Benning, PhD, a research fellow in the Department of Molecular Biology at Massachusetts General Hospital, is the first author of a new study in Nature Communications, Helical Reconstruction of VP30 Reveals Principles for Baculovirus Nucleocapsid Assembly. Luke Chao, PhD, is senior author of the study.

Summary:

Viruses are experts in attacking organisms. To protect their genome, which contains the blueprint for making all tools needed for host infection, viruses build a protein cage (a nucleocapsid) around it.

We discovered the architecture of an insect virus (baculovirus) nucleocapsid, by using an electron microscope, which unlike light microscopes, enables us to see the tiny protein machines of a cell.

Like a LEGO model, our structure explains how the nucleocapsid is built. This will help to improve the properties of baculoviruses, which are used to produce vaccines for therapeutic gene delivery in some cancers and as safe biological pesticides.

What Question Were You Investigating with this Study?

What is the architecture of the nucleocapsid of baculoviruses (insect viruses with wide ranging health and agricultural applications)?

What Methods or Approach Did You Use?

We used electron cryomicroscopy (cryo-EM) and a specific approach called helical reconstruction, which is used to determine the 3-dimensional structure of helical macromolecular assemblies.

Our approach was unique in that our sample, the baculoviral nucleocapsid, varies widely in diameter, which makes structure determination by cryo-EM very challenging.

Scientists have been trying since the early 1980s to determine an interpretable structure of these baculoviral nucleocapsids with no success until now.

Given these challenges, we had to use a combination of special sample enrichment techniques and advanced computational algorithms to determine the structure of the nucleocapsid.

What Were the Results?

Beyond the technical feat of this work, we gained valuable biological insights:

1. We found that dimers of the major capsid protein VP39 assemble into a 14-stranded helical tube to form the nucleocapsid
2. We found that the repeating subunit of the nucleocapsid, VP39, has a unique protein fold, which does not resemble any other viral protein folds
3. Determining the protein fold of the capsid protein VP39 reveals a possible binding site for the viral genome, which may explain where the viral genome binds in the nucleocapsid
4. We found that the protein fold of the major capsid protein VP39 is conserved across all baculoviruses, suggesting that our work provides insight into general principles of how all baculoviral nucleocapsids assemble
5. Finally, through analysis of the sample polymorphism we show that VP39 assembles in several closely-related helical geometries.

What are the Clinical Implications?

Baculoviruses are used as tools in therapeutic gene delivery and are now increasingly being developed as tools for cancer therapy (especially glioblastoma and brain cancer).

Furthermore, they are established biotechnological tools for vaccine production and heterologous protein production.

Our structure provides a first comprehensive model that could serve to improve these important therapeutic tools.

Moreover, Baculoviruses are biosafe and highly specific biological pesticides with growing economic significance and importance to due increased insecticide resistance.

Insects targeted by these insecticides are responsible for crop damages of billions of dollars in the US alone (even more so in countries in the Southern hemisphere).

Our structure of the baculoviral nucleocapsids now provides a blueprint of how to improve insecticides.

While agriculture may seem removed from human health, it is not.

Better and safer pesticides may ultimately, hopefully, reduce crop damage (reducing diseases associated with economical and existential burdens) and hunger epidemics.

What are the Next Steps?

Honestly, this work was a complete surprise discovery while we were working on something else. Therefore, our team does not plan on continuing this work.

Nonetheless, it would be interesting to now find out how the baculoviral nucleocapsid invades a host cell's nucleus.

Paper Cited:

Benning, F. M. C., Jenni, S., Garcia, C. Y., Nguyen, T. H., Zhang, X., & Chao, L. H. (2024). Helical reconstruction of VP39 reveals principles for baculovirus nucleocapsid assembly. Nature communications, 15(1), 250. https://doi.org/10.1038/s41467-023-44596-y

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.