New Model of Human Epstein-Barr Virus Infection Helps Explain How EBV Works

How does the Epstein-Barr Virus (EBV) manipulate our immune cells during initial infection? A new “human-tonsil-in-a-dish” model offers insights.

Chances are you have Epstein-Barr virus (EBV). It’s one of the most common human viruses, infecting 95% of the world’s population.

“Most people never have any symptoms, but a subset of people who are infected go on to have more serious cases,” says Lisa Wagar, PhD, an associate professor of physiology and biophysics at the UC Irvine School of Medicine. There is no vaccine for the lifelong infection, which can cause infectious mononucleosis (mono) and is strongly linked to several more serious conditions, such as certain cancers (lymphomas, stomach cancer and nasopharyngeal cancer) and autoimmunity.

“EBV infects human B cells, which are the antibody-producing cells of the immune system, and effectively hijacks their normal cellular functions to survive and hide in the body,” says Wagar. “A key unknown is understanding how EBV manipulates our immune cells during the initial infection event.”

That is what researchers in the Wagar Lab, collaborating with Ben Gewurz, MD, PhD, and his team at Brigham and Women’s Hospital of Harvard Medical School, set out to explore.

They outline their findings in a paper that appears in Proceedings of the National Academy of Sciences (PNAS).

A New Tonsil Organoid Model

It is difficult to study the very first events of an initial EVB infection for two main reasons:

1. People are usually asymptomatic and thus don’t know they are infected.
2. The initial infection happens in the tonsil, so it’s hard to sample.

“We used a ‘human-tonsil-in-a-dish’ model — or ‘tonsil organoids’ — to study how EBV infection works,” says first author Mahina Mitul, PhD, who was advised by Wagar while earning her PhD at UC Irvine and just started a postdoctoral fellowship at the National Institutes of Health (NIH).

“This is a new, very useful model of human EBV infection,” says Mitul. “The tonsil organoids we’re using closely mimic the actual environment in the body where EBV infection initially takes place.”

They made several important observations.

“EBV-infected B cells are very different from uninfected B cells but also very heterogeneous in the different states they take on during infection,” says Wagar, “even though at the surface level, they mimic many of the typical signals normal B cells receive in the tonsil.”

They also learned that CD4 T cells are important in controlling the outgrowth of EBV-infected B cells.

“There is a lot of excellent science on the role of CD8 T cells in controlling infection, but our studies from tonsil organoids show a perhaps underappreciated role for CD4 T cells in controlling the infection in the tonsil,” says Wagar.

Next Steps

In the future, the researchers plan to use the model to understand how the virus continues to manipulate B cells at different stages of the infection.

“In particular, we want to understand how the virus transitions from the initial infection stages to a long-term, latent and hidden state,” says Wagar. “We also plan to explore the link between EBV infection and the risk of cancer/autoimmunity using our organoid models.”

This work was funded in part by the Wellcome Leap HOPE (Human Organs, Physiology, and Engineering) program, the National Institutes of Health (NIH), and a UC Irvine Graduate Division fellowship.

— Shani Murray