New Study Highlights Immature Immune Barrier’s Role in Neonatal Viral Meningoencephalitis
A recent study published in Science Immunology sheds light on the factors contributing to viral meningoencephalitis in neonates. Research has shown that an immature immune barrier in the central nervous system (CNS) facilitates the entry of viruses in neonatal mice, leading to fatal infections. The study, conducted by a team of researchers, examined the lymphocytic choriomeningitis virus (LCMV) model to observe how viruses propagate within the CNS during systemic infection.
The researchers compared the structural and functional differences in CNS borders between four and eight-week-old adult mice and postnatal day seven neonates. The LCMV model was chosen as it allowed the researchers to observe the invasion of pathogens from the periphery without destroying CNS barriers.
Multiple barriers, such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier, normally protect the CNS from hematogenous pathogens that cause meningitis. However, systemic pathogens can sometimes breach these barriers and invade the CNS, resulting in uncontrolled immune cell trafficking. Therefore, it is crucial to understand how this breach occurs and to explore the mechanisms involved.
Previous studies have examined the perivascular spaces of the choroid plexus (CP) and leptomeninges as the primary sites of systemic virus entry into the CNS. However, these studies were conducted on human models infected through intracranial inoculation, which does not reflect the natural infection route. Other studies have focused on long-term neuroinfections that do not accurately represent real-world CNS infections. To address these limitations, the researchers used a murine model and systematically injected LCMV to simulate a natural infection.
The study also sought to elucidate the role of CNS border-associated macrophages, specifically the major histocompatibility complex class II (MHCII)hi and MHCIIlo macrophages, in serving as immune barriers and facilitating monocyte infiltration during pathogen invasion. By comparing resident immune cells and using single-cell RNA sequencing (scRNA-seq), the researchers characterized the immune and endothelial cells in the CNS. They also examined the depletion of specific immune cell populations and identified critical cell types involved in viral invasion of the CNS border tissues.
The results of the study revealed that MHCIIhi macrophages located at the dura’s perisinus prevent early invasion of the CNS by activating type 1 interferon (IFN)-mediated signaling. In neonates, the immaturity and poor recruitment of these macrophages compromise the establishment of the immune barrier at the perisinus, thereby facilitating viral entry into the CNS from the systemic circulation. This heightened vulnerability in neonates leads to a higher mortality rate compared to adult mice.
The study’s findings challenge previous notions about how systemic pathogens enter CNS border tissues. While previous studies focused on pathogen entry via the BBB and BCSFB, this study highlights the perisinus as the route for pathogen invasion. The researchers noted that the subarachnoid space in the perisinus is especially susceptible to pathogen invasion from the systemic circulation.
In conclusion, this study provides valuable insights into the mechanisms behind fatal meningoencephalitis in neonatal mice. The immaturity of the perisinus innate immune barrier, particularly the MHCIIhi macrophages, contributes to viral entry into the CNS during systemic viral infections. Establishing and maintaining this immune barrier is crucial in preventing CNS infections caused by viruses. Further research should explore the role of MHCIIhi macrophages in protecting against other systemic infections that compromise CNS barrier tissues. By understanding these mechanisms, we can develop strategies to protect neonates and improve outcomes for patients at risk of viral meningoencephalitis.
