To study cerebral immunity, researchers have become accustomed to administering infectious agents directly into the brain. At the Marseille Luminy Immunology Center, the team Inserm by Réjane Rua shows that the first stages are actually played out upstream, at the level of the brain. THE macrophages capture certain infectious agents there and effectively eliminate them, even before they enter the brain.
Réjane Rua’s team has been working for a long time with the lymphocytic choriomeningitis virus (CMLV), a pathogen that induces potentially fatal brain infections. To study the infectious mechanisms and the immune defenses activated by the host, she used to inject the virus into the heart of the mouse brain. But this strategy does not take into account the natural course of the infection: before entering it, the virus must first cross the membranes that surround the brain. The team therefore considered that it was time to take a closer look at the role played by these structures, called meninges, in the event of infection.
Work has shown that the meninges, long considered relatively inert from a functional point of view, are actually composed of a large number of immune cells such as dendritic cells, lymphocytes, mast cells and above all – the most abundant – macrophages. The latter are sentinels, armed to identify and sequester infectious agents. Their presence in number at the interface between the periphery of the body and the brain can logically suggest that they play an important role in cerebral immune defence. This is why Réjane Rua’s team decided to study, still in mice, the behavior of meningeal macrophages in response to the intrusion of different agents: the lymphocytic choriomeningitis virus, but also SARS-CoV‑ 2 responsible for Covid-19, or bacterial particles called LPS (for lipopolysaccharides). This time, no intracranial injection of the pathogens: their administration was carried out peripherally, in the blood of the animals, so as not to circumvent the natural border of the central nervous system.
Two populations of macrophages
The researchers combined several analysis methods to visualize the events induced by the infection, characterize the subpopulations of macrophages present, or even describe the gene expression profiles of the latter, before and after the infection. This work has highlighted the very good efficiency of macrophages in identifying the different pathogens tested. It also made it possible to distinguish two subpopulations of macrophages, which react differently to contact with an “enemy”. The first is present from the birth of animals and the second is gradually formed during the life of rodents. After having recognized the infectious agent, they present distinct gene expression profiles, which attest to the implementation of different, even complementary, mechanisms to counter the infection.
« Meningeal macrophages have the ability to stop infection dead in its tracks. The CMLV virus is thus eliminated in the meninges before any damage, whereas it is fatal if injected directly into the brain.notes Réjane Rua. This creates a paradigm shift: working on cerebral immunity now involves looking at the meninges as much as the brain “, she believes. From a clinical point of view, this work provides interesting information: Young children are more vulnerable to meningitis than adults. We speculated that this was related to a problem with the tightness of the blood-brain barrier, which would facilitate the passage of the pathogen from the periphery to the brain. In reality, this pediatric peculiarity could be attributable to the absence of the second population of macrophages at the beginning of life, which would reduce the efficiency of the meninges to fight against infections. “, she offers. This hypothesis also opens the way to a therapeutic avenue: Injecting factors produced by this second class of macrophages could help younger children fight infection », foresees Réjane Rua.
Réjane Rua is head of the Central Nervous System Immunosurveillance team at the Marseille Luminy Immunology Center (unit 1104 Inserm/CNRS/Aix-Marseille University).
Source : J. Rebejac et coll. Meningeal macrophages protect against viral neuroinfection. Immunityonline edition of 1is November 2022. DOI:10.1016/j.immuni.2022.10.005