Periodic Reporting for period 4 - VIROME (Shaping of long term innate immunity by viral education of bone marrow monocytes)
Période du rapport: 2024-07-01 au 2025-12-31
1. Context, problem, and overall objectives
The recent pandemic has shown that people can respond very differently to infections. A major reason for this is environmental exposure, especially to microbes such as viruses, which play a key role in shaping our immune system.
Although often overlooked, viruses can leave long-lasting “imprints” on immunity. These imprints can influence how susceptible individuals are to diseases later in life. There is strong evidence that past infections can “train” the innate immune system over the long term. Among the cells affected, monocytes are particularly important. These cells perform essential functions, including fighting infections, regulating inflammation, and maintaining tissue health.
Understanding these processes is important for society because it may explain why individuals differ in their risk of disease and could help improve prevention and treatment strategies.
The overall objective of this ERC project is to understand how and where viruses shape the development and function of monocytes, and how this affects long-term immunity. To achieve this, the project is structured around three main goals.
First, we characterize monocytes and their precursors using advanced techniques, including single-cell analyses, to better understand how viruses influence these cells.
Second, we investigate the molecular mechanisms behind this process, with a particular focus on interactions occurring in the bone marrow.
Third, we study the consequences of virus-induced changes in monocytes, both during the initial infection and in other, unrelated immune responses.
The recent pandemic has shown that people can respond very differently to infections. A major reason for this is environmental exposure, especially to microbes such as viruses, which play a key role in shaping our immune system.
Although often overlooked, viruses can leave long-lasting “imprints” on immunity. These imprints can influence how susceptible individuals are to diseases later in life. There is strong evidence that past infections can “train” the innate immune system over the long term. Among the cells affected, monocytes are particularly important. These cells perform essential functions, including fighting infections, regulating inflammation, and maintaining tissue health.
Understanding these processes is important for society because it may explain why individuals differ in their risk of disease and could help improve prevention and treatment strategies.
The overall objective of this ERC project is to understand how and where viruses shape the development and function of monocytes, and how this affects long-term immunity. To achieve this, the project is structured around three main goals.
First, we characterize monocytes and their precursors using advanced techniques, including single-cell analyses, to better understand how viruses influence these cells.
Second, we investigate the molecular mechanisms behind this process, with a particular focus on interactions occurring in the bone marrow.
Third, we study the consequences of virus-induced changes in monocytes, both during the initial infection and in other, unrelated immune responses.
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.
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.
The results generated by this project revealed new insights into the mechanisms underlying the long-term training of monocytes and monocyte-derived cells during gammaherpesvirus infection. Beyond these persistent gammaherpesvirus infections, the multi-omics data generated from lung macrophages and monocytes following four distinct viral infections form the basis for the development of a resource paper that will be of major interest as a single-cell–scale atlas, both for fundamental and applied research.
In addition, the findings obtained at the level of the bone marrow allowed refinement of the concept of innate immune memory by introducing greater nuance and complexity beyond the pre-existing concepts of priming or training effects. Finally, the demonstration of long-term functional consequences of monocyte imprinting at sites independent of viral replication sites represents a surprising finding that opens up very promising perspectives for future medical research.
In addition, the findings obtained at the level of the bone marrow allowed refinement of the concept of innate immune memory by introducing greater nuance and complexity beyond the pre-existing concepts of priming or training effects. Finally, the demonstration of long-term functional consequences of monocyte imprinting at sites independent of viral replication sites represents a surprising finding that opens up very promising perspectives for future medical research.