Neuroinflammatory Responses in Glial-Immune Interactions to Francisella tularensis in the Central Nervous System microenvironment 2267481

Abstract Introduction Francisella tularensis (Ft), the causative agent of tularemia, is a highly infectious intracellular pathogen and recognized Tier 1 Select Agent due to its low infectious dose, multiple routes of transmission, and potential use in bioterrorism. While Ft’s role in systemic inflammation is well established, its impact on the central nervous system (CNS) and its interaction with brain-resident immune cells is unknown. Methods This study investigates the neuroinflammatory response of glial and immune cells to Ft infection using an in vitro co-culture model that mimics the CNS microenvironment. Specifically, this study explores how Ft affects the inflammatory behavior of microglia, astrocytes, and macrophages individually and in combination following Ft infection and through the quantification of inflammatory cytokine production, thus characterizing glial-immune responses, and identifying mechanisms by which Ft may disrupt CNS homeostasis. Results Our findings suggest that Ft infection induces strong pro-inflammatory signaling among CNS-resident cells and emphasizes the importance of using multicellular models to study neuroimmune responses to infection. Notably, astrocytes influence microglial and macrophage immune responses through the release of soluble factors. This paracrine communication enhances cytokine production and inflammatory activation in these immune cells without direct cell contact, contributing to amplified neuroinflammation. Conclusion This work provides foundational insight into Ft-mediated neuroinflammation and supports further investigation into mechanisms of blood-brain barrier (BBB) disruption and bacterial persistence within the CNS. Insights from this model may inform future strategies to mitigate Ft-induced neurological damage and guide development of targeted therapeutics. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)