Research News

A collaboration between Ghent University in Belgium and Cleveland Clinic’s Florida Research & Innovation Center (FRIC) found a new way genetics influence the body’s antiviral response by studying a life-threatening disease caused by a common virus: herpes simplex virus 1 (HSV-1).

The researchers analyzed genetic data from a nine-month-old child with immunodeficiency who was hospitalized with herpes encephalitis, a rare-but-life-threatening brain inflammation after HSV-1 infection. They identified novel mutations in the gene GTF3A and found that these mutations impair the innate immune response.

The findings, published in Science Immunology, hold potential as a genetic marker doctors could use to gage a child’s risk of herpes encephalitis, although such mutations are generally very rare.

Many children are infected with the HSV-1 virus, but the vast majority don’t suffer from herpes encephalitis. The most common symptom of HSV-1 is oral cold sores, though many people show no signs at all. HSV-1 is more threatening to children and adults who are immunodeficient, or those whose immune system cannot control the virus well.

“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” says Michaela Gack, PhD, FRIC’s scientific director. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”

The Ghent research team led by Filomeen Haerynck, MD, PhD, reached out to Dr. Gack’s team after finding the mutations in the gene. Dr. Gack’s lab studies interactions between the human immune system and viruses on a molecular level.

The GTF3A mutations shape how cells respond to viral activity through the genetic makeup of a protein called TFIIIA. TFIIIA plays a role in helping a human enzyme produce certain types of RNA, which can determine specific functions within cells. Some RNA can elicit an anti-herpes viral immune response.

Dr. Gack’s team tested cells that have the mutations and found that because of defects in certain immunostimulatory RNAs, the cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.

The affected gene is part of the body’s defense system that produces interferons, or proteins that suppress virus infections and spread, and are crucial to the human immune response.

This new genetic pathway could be helpful in understanding the immune response to other viruses, like Epstein-Barr, a common virus linked to mononucleosis and associated with certain types of cancer and multiple sclerosis.

“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections,” Dr. Gack says. “Our findings on critical immune defense proteins may translate into new therapies in the future.”

The study was funded through U.S. National Institutes of Health grants AI165502 and AI087846, and the Flanders Institute for Biotechnology (VIB) Grand Challenges program. The award from VIB, an entrepreneurial non-profit research institute, is to Ghent University.