Pathogenesis of Acute CNS infection and injury

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Many inflammatory processes profoundly influence central nervous system (CNS) function and contribute to human disease. Acute CNS infections, for instance, can precipitate meningitis, encephalitis, and other life-threatening conditions. A central interest of our laboratory is to mechanistically define how acute infections affect the CNS and to identify therapeutic strategies that mitigate the resulting neurological damage. Our studies span diverse pathogens—including viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus), parasitic (Plasmodium berghei), and fungal (Candida albicans) infections—to dissect how the immune system responds to distinct challenges. Ultimately, we aim to strengthen host defenses, uncover why immune protection sometimes fails, and develop interventions that support CNS recovery following pathogen clearance. In addition to infections, a major research priority in our laboratory is the immunology of CNS injuries and the degenerative conditions that arise when repair is incomplete. We investigate both traumatic brain injury (TBI) and cerebrovascular injury (CVI), with the goal of identifying therapeutic approaches that limit acute damage while promoting long-term functional repair. Given the essential role of vascular integrity in CNS health, we explore immunological pathways that drive vascular repair in the injured brain and meninges. In parallel, we assess how environmental variables, such as concurrent infections, alter repair trajectories and influence recovery outcomes. We have uncovered key mechanisms underlying cerebrovascular injury (CVI) repair. In humans, stroke, intracerebral hemorrhage, and traumatic brain injury (TBI) all cause vascular damage requiring restoration. To investigate how repair occurs, we focused on the crosstalk between peripheral monocytes and microglia in rebuilding damaged vessels. In human stroke lesions, we mapped pro-angiogenic VEGFA⁺ repair-associated microglia (RAM) within the penumbra and analyzed their spatial relationship to injured cortical vessels in rodent CVI models. We identified interleukin-6 (IL-6), released by monocytes/macrophages, as a key cytokine that reprograms microglia into pro-angiogenic, proliferative RAM. IL-6 signaling promoted RAM generation, enabling effective vascular repair and functional recovery. Single-cell transcriptomic profiling revealed that CVI activates diverse signaling pathways in microglia and monocyte-derived macrophages, including IL-6, TNF, and type I interferon. Notably, RAM displayed a robust pro-angiogenic gene signature and high proliferative activity. Disruption of IL-6 signaling or loss of CCR2⁺ monocytes blocked RAM formation, leading to impaired repair, blood–brain barrier leakage, neural cell death, fibrosis, and poor recovery. Importantly, exogenous IL-6 treatment restored RAM generation and vascular remodeling in the absence of CCR2⁺ monocytes. Together, our findings demonstrate that IL-6-driven VEGFA⁺ RAM are essential for cerebrovascular repair and functional brain recovery after CVI and highlight a therapeutic opportunity to enhance RAM generation for improved outcomes. We also recently advanced our understanding of how immunologically active CNS barrier structures, particularly the meninges, protect the parenchyma from peripheral infections. While most CNS blood vessels are sealed by tight junctions to block toxins and microbes, the outermost meningeal layer—the dura mater—contains fenestrated vasculature lacking such seals. These fenestrations permit the passage of fluids, molecules, cells, and potentially circulating pathogens, posing a direct risk to underlying neural tissue. We found that large venous sinuses and vascular plexuses in the dura mater, which form part of the CNS drainage system, are highly fenestrated and vulnerable to microbes up to 2 µm in size. To counter this threat, these regions are fortified by abundant innate and adaptive immune cells. In fact, organized immune hubs form around complex dural vascular plexuses, functioning as surveillance and rapid-response sites where drainage vessels converge. Remarkably, these hubs also support local B cell maturation through germinal center reactions, thereby enhancing antibody responses to invading pathogens. When such defenses fail, pathogens can penetrate beyond the dura, leading to severe infections such as meningitis and encephalitis. Thus, dural immune hubs surrounding fenestrated vasculature represent critical protective niches for CNS health and offer potential targets for vaccine strategies aimed at preventing neuroinvasive infections. A further direction of our research centers on the dural venous sinuses. Traditionally regarded as passive blood drains for the brain and skull, these structures instead exhibit remarkable adaptability. Using intravital microscopy, we found that dural sinuses and their associated endothelial cells form an actively remodeling surface that regulates blood flow, fluid exchange, and immune surveillance. Contrary to the assumption of passivity, we observed that sinuses constrict and dilate under RAMP1-dependent smooth muscle control, analogous to arterial regulation. Furthermore, the murine superior sagittal sinus is divided into upper and lower chambers lined by specialized, fenestrated endothelial cells that enable the passage of fluids, macromolecules, and microbes into leukocyte-rich perisinus spaces. To safeguard this permeable interface, sinus endothelial cells (SECs) regulate their boundaries through RAMP2-dependent mechanisms. Disruption of this process via transcranial RAMP2 antagonism impaired SEC dynamics and immune cell trafficking under steady-state conditions and during systemic viral infection. Interference with SEC function during infection compromised local antiviral immunity and permitted pathogen entry into the meninges. In concert, these findings establish dural sinuses as adaptive vascular structures with specialized SECs that coordinate fluid regulation, immune surveillance, and protection against infection.