A novel drug target for viral encephalitis therapies
Researchers showed CXCL1 signalling to neutrophils drove brain inflammation in herpes simplex virus (HSV) encephalitis and blocking the protein resulted in less severe disease.
According to a new study, targeting the CXCL1 signalling protein could be a therapeutic approach for preventing brain damage and death due to the most common cause of viral encephalitis worldwide, herpes simplex virus (HSV).
HSV, which causes cold sores, is also associated with an extreme complication in which inflammation in the brain causes severe brain damage that is fatal in most cases, despite rapid anti-viral treatment. HSV encephalitis takes hold quickly and survivors are left with brain injuries due to the inflammation and damage caused by the virus and immune cells gaining access to the brain, breaking down the blood-brain barrier.
In a new study published in Cell Reports, researchers at the University of Liverpool, UK, identified that neutrophils, a type of immune cell that circulates in the blood, induces brain inflammation in HSV encephalitis. They also determined the signalling protein that drives these immune cells to migrate into the brain from the bloodstream, a finding that could aid the development of targeted treatments for the most common cause of viral encephalitis worldwide.
“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,” explains Dr Benedict Michael, a Senior Clinician Scientist Fellow at the University of Liverpool, who led the research.
Using a mouse model, the researchers showed that neutrophils made the blood-brain barrier more permeable and contributed to the brain damage associated with HSV encephalitis. Unlike monocytic immune cells which the team found protected against HSV (controlling the virus and preventing brain damage), these neutrophils were not needed to control the virus.
The team also identified that CXCL1 was the signalling protein that drove the migration of these damaging neutrophils into the brain during HSV infection. By blocking signalling by the CXCL1 protein, neutrophils were prevented from crossing the blood-brain barrier and causing inflammation, resulting in less severe disease.
The team stated that their findings make the CXCL1 protein an attractive target for new therapies that can stop the influx of damaging white blood cells without limiting the roles of protective ones.
Dr Michael said: “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. 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.”
Now the team intend to examine the impact of the CXCL1 signalling protein in patients who have already had steroids as part of a clinical trial led by Professor Tom Solomon at the University of Liverpool.