Observational studies of psychiatric diseases such as schizophrenia, bipolar disorder and major depression have long tied viral infections with behavioral symptoms in these disorders, but scientists have been unable to find direct evidence of suspected viruses in the brain. Experts say that's possibly because viruses may not get directly inside the brain, but may target the brain lining instead.
After testing that idea using postmortem human brain samples and the electronic medical records of 285 million patients, a team of Johns Hopkins Medicine scientists says it has found such evidence in the form of the liver-damaging hepatitis C virus in the human brain's choroid plexus, a collection of cells that make up the lining of the fluid-filled cavities, or ventricles, and — notably — produce the cerebrospinal fluid that protects the brain and spinal cord.
A report on the study, led by investigators at Johns Hopkins Children's Center , published July 14 in Translational Psychiatry.
The findings confirm previous studies that reported higher than usual hepatitis C (HCV) prevalence in people with schizophrenia or bipolar disorder, and suggest that HCV infections may be associated with the cause of disease rather than behaviors such as intravenous drug use, according to the Johns Hopkins team led by Sarven Sabunciyan, Ph.D. , a neuroscientist at the Children's Center and an associate professor of pediatrics at the Johns Hopkins University School of Medicine.
For the study, the team first analyzed choroid plexus samples from postmortem brains of individuals with schizophrenia, bipolar disorder or major depression, as well as unaffected controls. The samples were obtained from the Stanley Medical Research Institute collection, a widely used postmortem repository of brain tissue from people with mental health disorders.
They then performed high-throughput sequencing using the Twist Comprehensive Viral Research Panel, a commercial technology that enables identification of more than 3,000 viruses in human samples.
Because previous psychiatric disorder studies had failed to identify viruses inside the brain, the researchers specifically focused on the choroid plexus, which is known as a structure that is targeted by viruses. The analysis revealed the presence of various viruses in the choroid plexus.
The researchers found that more viruses were present in samples from people with schizophrenia or bipolar disorder. But, unlike other viruses, HCV was only present in the brain lining of people who had schizophrenia or bipolar disorder. Notably, the virus was not present in some individuals who were known to have a chronic HCV diagnosis, suggesting that the infection does not always spread to the brain lining.
HCV infection is common, generally contracted through infected blood, and characterized by inflammation of the liver that can lead to serious complications and even death. An estimated 50 million people have chronic HCV infections worldwide, with about 1 million new infections occurring each year. About 50% to 75% of cases carry no symptoms. The infections are treatable with antiviral drugs.
Bipolar disorder, characterized by episodes of manic behavior and serious depression, is estimated to have affected approximately 9 in 200 adults in the U.S. at some time in their lives, while schizophrenia, marked by disorganized thinking and hallucinations, and related psychotic disorders are estimated to affect between 1 and 3 in 400 adults in the U.S.
During the next phase of the study, the research team analyzed electronic health records held by TriNetX, and found that HCV was documented in 3.6% of those with schizophrenia and 3.9% of those with bipolar disorder — almost double that of those with major depression (1.8%), and approximately sevenfold higher than the control population (0.5%). The researchers say while illicit drug use is common among people with all three disorders, drug use did not account for the higher prevalence of HCV in schizophrenia and bipolar disorder compared with major depression.
The team also looked for viral RNA in sequencing data from the hippocampus, a region of the brain that supports learning, memory and other functions, of subjects identified to have HCV, and found that the virus was absent in this tissue despite being present in the brain lining. However, the presence of HCV in the brain lining altered gene expression in the hippocampus, providing a possible mechanism by which an infection in the lining can affect brain functions and behavior.
While the researchers caution that their study does not suggest that everyone with schizophrenia or bipolar disorder has an HCV infection, they believe their findings provide compelling support for the existence of the virus in the choroid plexus.
"Our findings show that it's possible that some people may be having psychiatric symptoms because they have an infection, and since the hepatitis C infection is treatable, it might be possible for this patient subset to be treated with antiviral drugs and not have to deal with psychiatric symptoms," Sabunciyan says.
He says he also hopes to collaborate with mental health professionals to screen for HCV in people with bipolar disorder and schizophrenia to learn whether treating the infection will ease or stop symptoms.
Along with Sabunciyan, authors from the Johns Hopkins University School of Medicine are Ashwin Balagopal, Ou Chen and Jeffrey Quinn. Maree Webster from the Stanley Medical Research Institute was also a co-author.
This study was funded by grants from the Stanley Medical Research Institute.
No authors declared conflicts of interest under Johns Hopkins University School of Medicine policies.
DOI: 10.1038/s41398-025-03387-3
