In a recent study, researchers from Uppsala University show that the Semliki Forest virus enters the central nervous system by first entering the cerebrospinal fluid and then binding to a specific cell type before penetrating deeper into the brain. This finding could potentially be used to develop the Semliki Forest virus as an agent to treat brain cancer. The study has been published in the journal Nature communications.
Semliki Forest virus was originally isolated from mosquitoes in Uganda’s Semliki Forest, hence the name. After systemic infection from mosquito bites, Semliki Forest virus causes mild blood viremia before finding its way to the central nervous system where it can cause neurotoxicity.
It has been a long quest in virology to discover how the Semliki Forest virus enters the brain, but it has been suggested that it occurs through the blood-brain barrier. A few years ago, a receptor called Very Low Density Lipoprotein Receptor (VLDLR) was identified as the main receptor for Semliki Forest virus when it enters host cells.
It reaches the brain in the same way as other viruses
In the current study, the Uppsala researchers verified VLDLR as the main cell entry receptor. But since VLDLR is not expressed by blood vessel cells at the blood-brain barrier, they argued that there must be another way for Semliki Forest virus to enter the central nervous system. They confirmed this by identifying choroid plexus cells, the cell type that secrete cerebrospinal fluid into the ventricles of the brain, as a gateway for neuro-invasion.
“Passage of Semliki Forest virus through the choroid plexus epithelial cell layer is strictly dependent on VLDLR. This neuro-invasion pathway has been demonstrated for other viruses, such as ZIKA and SARS-CoV-2, but our study is first to demonstrate that the Semliki Forest virus can also use this route to enter the central nervous system,” says Miika Martikainen, researcher at Uppsala University, who is first and corresponding author of the publication.
It could be used to treat brain tumors
Oncolytic viruses are used as cancer immunotherapy, where the virus invades and kills cancer cells and activates the immune system to attack the tumor. Since Semliki Forest virus penetrates the brain, it is an interesting candidate to be developed as an oncolytic agent for the treatment of brain cancers.
I have been working with the Semliki Forest virus for many years and I am very happy that we were able to solve this question. We will now focus our work on developing the Semliki Forest virus as a therapeutic agent for cancer.”
Miika Martikainen, researcher, Uppsala University
When the researchers tested how well different viruses activated the immune system, the Semliki Forest virus was by far the best. However, it has never before been clinically tested in the treatment of cancer.
“The new knowledge gained from our study could have direct implications for how the Semliki Forest virus could be transmitted to patients with severe brain tumor glioblastoma in a clinical trial,” says Magnus Essand, researcher at Uppsala University and senior author of the paper.
Source:
Journal Reference:
Martikainen, M., et al. (2024). VLDLR mediates Semliki Forest virus neuroinvasion through the blood-cerebrospinal fluid barrier. Nature communications. doi.org/10.1038/s41467-024-55493-3.
