Route of entry for Semliki Forest virus into the brain revealed
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 can potentially be used to develop the Semliki Forest virus as an agent for treating brain cancer. The study has been published in the journal Nature Communications.
Miika Martikainen and Magnus Essand (photo: Private, Mikael Wallerstedt)
Semliki Forest virus was originally isolated from mosquitoes in the Semliki Forest, Uganda, hence the name Semliki Forest virus (SFV). Upon systemic infection from mosquito bites, SFV causes mild blood viremia before it finds its way to the central nervous system (CNS) where it can cause neurotoxicity.
It has been a longstanding quest in virology how the SFV enters the brain but it has been suggested to occur through the blood–brain barrier. A few years ago, a receptor called Very Low-Density Lipoprotein Receptor (VLDLR) was identified as the primary receptor for SFV when entering host cells.
In the current study, the Uppsala researchers verified VLDLR as the primary cell entry receptor. But since VLDLR is not expressed by blood vessel cells in the blood-brain barrier they reasoned that there must by another way for SFV to enter the CNS. They confirmed this by identifying choroid plexus cells, the cell type that secrete cerebrospinal fluid into the ventricles of the brain, as the gateway for neuro-invasion.
“Passage of SFV through the epithelial cell layer of the choroid plexus is strictly dependent on VLDLR. This route of neuro-invasion has been demonstrated for other viruses, such as ZIKA and SARS-CoV-2, but our study is the first to demonstrate that SFV can also use this route to enter the CNS,” says Miika Martikainen, researcher at the Department of Immunology, Genetics and Pathology, who is first and corresponding author of the publication.
Treatment for brain cancers
Oncolytic viruses are used as an immunotherapy against cancer, where the virus both invades and kills cancer cells, and activates the immune system to attack the tumour. Since SFV penetrates into the brain it is an interesting candidate to be developed as an oncolytic agent for the treatment of brain cancers.
“The new knowledge gained from our study can have direct implications for how SFV could be delivered to patients with the severe brain tumour glioblastoma in a clinical trial,” says Magnus Essand, senior author of the paper.
“I have been working on SFV for many years and I’m very pleased that we have been able to solve this question. We will now focus our work on developing SFV as a therapeutic cancer agent,” says Miika Martikainen.