Researchers have identified the specific type of immune cell that causes brain inflammation in herpes simplex virus (HSV) encephalitis, a condition widely known as the cold sore virus, which causes inflammation and swelling of the brain.
They have also determined the protein that calls this immune cell into the brain from the bloodstream, causing brain infection, which is the most common cause of viral encephalitis.
The findings, published in Cell Reports, explain that HSV kills a lot of patients. Those who survive are often left with brain injury due to the inflammation and damage caused by the virus and immune cells gaining access to the brain, breaking down the blood-brain barrier.
“Determining the roles of specific immune cells and the factors that allow them to cross the protective blood-brain barrier is critical to develop targeted immune-therapies,” says Benedict Michael, senior clinician scientist fellow at the University of Liverpool, who led the research.
Researchers found that neutrophils, a type of immune cell, made the blood-brain barrier more permeable, which contributes to the brain damage found in HSV encephalitis patients.
They also identified the exact signalling protein (CXCL1) that drove these damaging neutrophils into the brain. By blocking this CXCL1 protein in mice, the researchers were able to see that neutrophils were prevented from crossing the blood-brain barrier and causing inflammation. This resulted in less severe cases of the disease.
“We set out to identify which immune cells are required to control the virus and which immune cells are not needed to control the virus but which do drive brain swelling,” Michael says.
“And crucially, which immune signals coming from the brain draw these cells in, and if blocking them can prevent brain swelling without impairing viral control.”
The findings put the spotlight on the CXCL1 protein as a potential target for new therapies that block the damaging proteins and let through the immune cells that help protect the body from the infection.
“There is currently no licenced treatment for the severe brain swelling which occurs, despite antiviral therapy in HSV encephalitis. Sometimes steroids are given, but as these suppress the immune system in a very broad way, there is a risk of uncontrolled viral infection,” Michael says.
“There is an urgent need for targeted treatment that prevents damaging immune cells from entering the brain without limiting the immune cells needed to control the virus.”
“I have seen so many patients succumb to viral encephalitis. They slip into a coma and many die as their brain scan shows increasing brain swelling to the point that it starts to herniate through the hole in the bottom of the skull,” Michael tells NR Times.
“As doctors, we worry that giving steroids to reduce this brain swelling might lead to uncontrolled viral replication and actually worsen the situation. Therefore, we desperately need medications which target those processes driving inflammation without hampering those aspects of the immune response which are required to control the virus.”
The researchers are planning to examine the impact of CXCL1 in patients who have already had steroids as part of a clinical trial led by Tom Solomon at the University of Liverpool. The team is randomising 90 patients with HSV encephalitis, half to steroids and half to a placebo.
“We are looking to see if steroids improve outcome in terms of brain function and also whether steroids reduce brain inflammation on neuroimaging, and crucially, which of the immune signalling proteins identified in our mouse model are affected and is viral replication prolonged due to immune suppression,” Michael says.
