Spatiotemporal control of neuroinfection by meningeal macrophages

Project Information

CNSentinels

Grant agreement ID: 949631

DOI

10.3030/949631

EC signature date 23 October 2020

Start date 1 May 2021

End date 31 October 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 912 500,00

EU contribution

€ 1 912 500,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - CNSentinels (Spatiotemporal control of neuroinfection by meningeal macrophages)

Reporting period: 2022-11-01 to 2024-04-30

Summary of the context and overall objectives of the project

Problem/Issue Being Addressed: The study aims to understand the dynamics, diversity, and functions of meningeal macrophages in the context of viral infections affecting the central nervous system (CNS). Specifically, the research investigates how these barrier macrophages respond to various viral challenges, such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV), and their role in preventing viral spread into the CNS.
Importance for Society:
1. Neurological Protection: Understanding the neuroprotective role of meningeal macrophages is crucial for advancing knowledge about the immune defense mechanisms in the CNS. This has implications for developing strategies to enhance the body's ability to protect the central nervous system from viral infections, which can have significant societal implications given the impact of neurological diseases.
2. Therapeutic Targets: If meningeal macrophages are identified as key players in preventing viral spread, this knowledge could lead to the development of targeted therapeutic interventions. Manipulating these macrophages could potentially enhance the body's natural defenses against viral infections in the CNS.
3. Public Health and Infectious Diseases: The study's findings may contribute to our understanding of how the immune system responds to viral challenges, including those associated with diseases such as SARS-CoV-2. Insights gained from this research could inform public health strategies for managing and preventing viral infections that impact the central nervous system.
Overall Objectives:
1. Characterization of Meningeal Macrophages: To comprehensively characterize the dynamics, diversity, and fate of meningeal macrophages in response to various viral challenges.
2. Understanding Temporal Changes: To investigate the temporal changes in MHC-II expression in meningeal macrophages and correlate them with the progression of viral infections.
3. Assessment of In Vivo Responses: To assess the in vivo responses of meningeal macrophages to peripheral challenges, including the asymptomatic response to peripheral LCMV infection.
4. Unraveling Mechanisms of Viral Spread: To understand the specific mechanisms by which meningeal macrophages contain viral spread into the CNS, and how their absence or dysfunction may lead to extensive viral dissemination.
5. Development of Targeted Interventions: To explore transcranial pharmacological depletion strategies targeting meningeal macrophages, aiming to understand their localized effects and potential as therapeutic interventions.
6. Correlation Studies: To establish correlations between the presence of specific macrophage subtypes, such as MHC-II+ macrophages, and the viral load upon infection.
The overall objectives are geared towards advancing our understanding of the immune response in the CNS, identifying potential therapeutic targets, and contributing to the broader field of neuroimmunology. The research may have implications for the development of strategies to protect against viral infections impacting the central nervous system.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The significant achievement in our study focuses on Border-associated macrophages (BAMs) and their role at the brain-periphery interface, specifically in the meninges. Here's a summary of the key accomplishments:
1. Characterization of BAM Dynamics, Diversity, and Fate:
• Our study thoroughly explores the dynamics, diversity, and fate of murine BAMs during infection. This includes an in-depth investigation into how these macrophages respond to various stimuli, their functional diversity, and their temporal behavior.
2. Assignment of a Neuroprotective Role to BAMs:
• A major achievement of our study is assigning a neuroprotective role to BAMs. This discovery implies that border-associated macrophages play a critical part in safeguarding the nervous system during infections. This finding holds significance for advancing our understanding of the immune response at the brain-periphery interface.
3. Advancement in Understanding Immune Response at Brain Periphery Interface:
• Our research contributes to the advancement of knowledge regarding the immune response at the interface between the brain and the periphery, particularly in the meninges and choroid plexus. This progress represents a substantial step forward in the field of neuroimmunology.
4. Highlighting Neuroprotective Functions of BAMs:
• By underscoring the neuroprotective role of BAMs, our study has the potential to shape future research directions and therapeutic strategies. Understanding the specific contributions of BAMs in protecting the nervous system opens avenues for developing interventions to enhance neuroprotection during infections.
In summary, our study achieves a comprehensive understanding of BAMs, unraveling their dynamics, diversity, and neuroprotective role during infection. This enhances our knowledge of the immune response at the brain-periphery interface and may hold broader implications for the field of neuroimmunology.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

As we approach the project's conclusion, we anticipate achieving outcomes that specifically enhance our understanding of neurodevelopment and the role of Border-associated macrophages (BAMs) in this context:
1. Identification of Key Regulatory Elements Influencing Neurodevelopment:
• Our research aims to identify key regulatory elements governing the neurodevelopmental aspects influenced by BAMs. This includes unraveling signaling pathways that play pivotal roles in shaping the nervous system during infection and homeostasis.
2. Identification of BAMs' Impact on Neurodevelopment Across Diverse Infection Models:
• We expect to explore the impact of BAMs on neurodevelopment across diverse infection models, encompassing various pathogens as well as steady-state. This will provide insights into how BAMs contribute to the intricate processes of neurodevelopment, fostering a nuanced understanding of their role.
3. Potential Therapeutic Strategies for Enhancing Neurodevelopmental Resilience:
• Building on our findings, we intend to explore the potential development of therapeutic strategies aimed at enhancing neurodevelopmental resilience. These strategies may involve targeted interventions to modulate BAM activity, presenting novel opportunities for mitigating the impact of infections on neurodevelopment.
In summary, our project's expected results center on advancing our understanding of neurodevelopment and the intricate role BAMs play in this process during infections. We anticipate identifying key regulatory elements, validating BAMs' impact across diverse infection models, gaining insights into neuroprotective mechanisms during development, and exploring therapeutic strategies to enhance neurodevelopmental resilience.