Aggregates of misfolded proteins, which are associated with neurodegenerative diseases and occur in prion diseases such as Creutzfeldt-Jakob disease, have the ability to pass from one cell to another—including unaffected cells. As a result, the disease spreads across the brain. Alzheimer’s and Parkinson’s diseases also exhibit assemblies of misfolded proteins. Transmission of aggregates could involve direct cell-to-cell contact, the release of proteopathic seeds into extracellular space, or secreted in association with extracellular vesicles (EVs). The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear.

“The precise mechanisms of transmission are unknown,” said Ina Vorberg, PhD, a research group leader at the DZNE’s Bonn site and professor at the University of Bonn. “However, it is an obvious guess, that aggregate exchange by both direct cell contact and via vesicles depends on ligand-receptor interactions. This is because in both scenarios, membranes need to make contact and fuse. This is facilitated when ligands are present that bind to receptors on the cell surface and then cause the two membranes to fuse.”

Now, Vorberg’s team has shown that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Their data, they say, raise the possibility “that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.”

This work is published in Nature Communications in the paper, “Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions.

The team investigated the intercellular transfer of either prions or aggregates of tau proteins, as they occur in similar form in prion diseases or Alzheimer’s disease and other “tauopathies.” Mimicking what happens because of viral infection, the researchers induced cells to produce viral proteins that mediate target cell binding and membrane fusion. Two proteins were chosen as examples: SARS-CoV-2 spike protein S and vesicular stomatitis virus glycoprotein VSV-G, which occurs in a pathogen that infects cattle and other animals. Moreover, cells expressed receptors for these viral proteins, namely the LDL receptor family, which act as docking ports for VSV-G, and human ACE2, the receptor for the spike protein.

“We could show that the viral proteins are incorporated both into the cellular membrane and into the extracellular vesicles. Their presence increased protein aggregate spreading between cells, both by direct cell contact or by extracellular vesicles. The viral ligands mediated an effective transfer of aggregates into recipient cells, where they induced new aggregates. The ligands act like keys that unlock the recipient cells and thus sneak in the dangerous cargo,” Vorberg said. “Certainly, our cellular models do not replicate the many aspects of the brain with its very specialized cell types. However, independent of the tested cell type producing the pathologic aggregates, the presence of viral ligands clearly increased the spreading of misfolded proteins to other cells.  All in all, our data suggest that viral ligand-receptor interactions can in principle affect transmission of pathologic proteins. This is a novel finding.”

“The brains of patients suffering from neurodegenerative diseases sometimes contain certain viruses. They are suspected to cause inflammation or to have a toxic effect, thus accelerating neurodegeneration. However, viral proteins could also act differently: They could increase intercellular spreading of protein aggregates already ongoing in neurodegenerative diseases like Alzheimer’s,” Vorberg said. “Of course, this needs further studies with neurotropic viruses. Clearly, the impact of viral infections on neurodegenerative diseases deserves in-depth investigation.”