The Epstein-Barr virus (EBV), a ubiquitous pathogen infecting an estimated 90-95% of the global population, has long been linked to an increased risk of certain cancers and autoimmune diseases. However, the precise mechanisms by which the body controls this persistent viral infection have remained largely elusive. Now, researchers at the University Hospital Bonn (UKB) and the University of Bonn have made significant strides in unraveling this mystery, identifying both genetic and non-genetic factors that influence the body’s ability to manage EBV infection. Their innovative approach involved repurposing existing genome sequencing data, originally collected for human genome characterization, to estimate the viral load of EBV in the blood and identify correlations within large health datasets.
EBV establishes a lifelong presence in the body, specifically residing in a latent state within B memory cells – a type of white blood cell. While typically inactive during this latency phase, the virus can reactivate under conditions of stress, transitioning to an active state. Despite its widespread prevalence and association with serious health conditions, a comprehensive understanding of how the immune system regulates this persistent infection has been lacking. “Despite its high relevance, very little is known about how exactly the immune system controls lifelong EBV infection and how this contributes to the development of diseases such as cancer or autoimmune diseases,” explains Professor Kerstin Ludwig, from the Institute of Human Genetics at the UKB, and a member of the ImmunoSenstation3 and the Transdisciplinary Research Areas (TRA) “Life and Health” & “Modeling” at the University of Bonn. “This is largely due to a lack of suitable data—for example, large population-based studies such as biobanks lack direct measurements of EBV viral load.”
The research team developed a novel method to estimate EBV viral load using genome sequencing data. This “repurposing” of existing data allowed them to analyze sequences from the blood of a substantial cohort – 486,315 participants in the UK Biobank and 336,123 participants in the All of Us project. They identified short DNA segments attributable to the EBV genome, termed “EBV reads,” in 16.2% and 21.8% of individuals, respectively. “People in whom such EBV reads are detected have, on average, an increased EBV viral load. We were able to demonstrate this with laboratory tests,” states Dr. Axel Schmidt, lead author from the Institute of Human Genetics at the UKB. “Since large biobanks, such as the UK Biobank, have collected genome sequencing data for all participants, we now have a measure with which the EBV viral load can be estimated on a large scale. This opens up completely new possibilities for investigating the many questions that still remain on the subject of EBV immunity.”
The study revealed several factors associated with EBV viral load. Notably, individuals with compromised immune systems and current smokers exhibited increased levels of the virus. Smoking, already recognized as a risk factor for EBV-associated diseases, has previously lacked a clear mechanistic explanation for this association. “Our data indicate that current smoking in particular increases EBV viral load,” says Dr. Schmidt. “Other groups have already shown that current smoking has an influence on the innate immune system. This could therefore be an indication that this interaction also plays a role in EBV control.” Interestingly, a seasonal correlation was also observed, with higher viral loads detected during winter months and lower loads in summer.
At the genetic level, the researchers identified a strong association between EBV viral load and the major histocompatibility complex (MHC) locus. The MHC region contains genes encoding proteins crucial for immune recognition of pathogens, making it a central player in immune responses. Beyond the MHC locus, associations were also found in 27 other genomic regions, largely consistent across both biobanks. These regions contain genes with known roles in immune function, as well as a number of previously uncharacterized candidate genes that may contribute to EBV control. Further analysis revealed genetic overlaps between EBV viral load and EBV-associated diseases, offering new insights into the potential mechanisms underlying multiple sclerosis (MS) and suggesting a possible role for EBV in conditions like type 1 diabetes.
Professor Ludwig emphasizes the significance of these findings: “Our results serve as a basis for understanding EBV immunity, and they also open up avenues for new mechanistic studies and therapeutic approaches for EBV-associated diseases. In a broader sense, our study illustrates how by-products of human genome sequencing data can be used to investigate persistent viral infections.”
The study, published in in the journal Nature, involved collaboration between the UKB and the University of Bonn, as well as the University of Tokyo in Japan. This research provides a valuable foundation for future investigations aimed at improving our understanding of EBV immunity and developing targeted strategies for preventing and treating EBV-related illnesses.
Recent research, published on , also highlights the broader impact of viral infections on the immune system. A study published in Nature demonstrated that smoking alters adaptive immunity with persistent effects, even after smoking cessation. This finding, alongside the current research on EBV, underscores the complex interplay between environmental factors, viral infections, and long-term immune function.
