2. Work performed and main results
This project investigated how persistent viral infections shape immune cells and influence long-term immunity. We focused on gammaherpesviruses, including Epstein–Barr virus (EBV), using mouse and humanized models to understand their impact on monocytes and their precursors.
We demonstrate that these viruses durably reprogram immune cells in the bone marrow at phenotypic, molecular, and epigenetic levels, leading to altered responses to later challenges. This process requires viral persistence and is driven by immune signals such as IFN-γ. During chronic infection, memory CD8⁺ T cells accumulate in the bone marrow and rapidly produce IFN-γ, creating a feedback loop that amplifies immune reprogramming. These findings reveal how persistent viruses establish a long-term equilibrium with the host immune system.
We then examined the functional consequences of this imprinting.
First, in antiviral responses, monocytes play a crucial role in controlling inflammation. In their absence, infections that are normally harmless can become severe due to uncontrolled immune responses. This effect depends on regulatory pathways that limit tissue damage.
Second, in the lungs, viral infections reshape the immune environment. We show that they can protect against allergic asthma by promoting the replacement of resident macrophages with regulatory monocyte-derived cells. They can also enhance protection against unrelated viral infections. However, in other contexts, such as lung fibrosis, viral imprinting worsens disease by promoting harmful interactions between immune and tissue cells, leading to increased tissue damage.
Third, beyond the lungs, viral imprinting also affects intestinal immunity. We show that infection induces a long-lasting expansion of highly active CD8⁺ T cells that accumulate in the intestine and contribute to inflammation. This process is associated with the recruitment of monocytes that further amplify immune responses. These findings are supported by results in humanized models and patient cohorts, linking persistent viral infection to disease severity.
Overall, the project demonstrates that viral imprinting of monocytes has broad and long-lasting effects across multiple organs, with outcomes that can be either protective or harmful depending on the context.
Dissemination and outreach
In addition to the accepted and ongoing publications and keynote lectures, research generated within this ERC project has been disseminated through seminars at the University of Liège, including ImmunoConnect 2025 and ERC information seminars for applicants. The work has also been communicated to the general public through popular science programs such as Les visages de la recherche and Les éclaireurs, as well as through articles published on the University of Liège website, the FNRS website, and the Belgian Research in Europe platform.
