Pathogenesis of Acute CNS infection and injury

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Many inflammatory processes directly impact central nervous system (CNS) function and give rise to human diseases. For example, acute CNS infection can induce a variety of diseases, such as meningitis and encephalitis. A primary interest in our laboratory is to mechanistically define the impact of acute infections on the CNS and establish treatments to ameliorate the associated neurological diseases. We study viral (lymphocytic choriomeningitis virus, vesicular stomatitis virus), parasitic (plasmodium berghei) and fungal (candida albicans) infections to determine how the immune system responds to these different challenges. We are ultimately interested in improving our immunological defenses against different pathogens, understanding why our immune system sometimes fails to protect us, and developing therapeutics that improve CNS recovery after infections are cleared. Another major focus of our laboratory is CNS injuries and the subsequent degenerative diseases that develop when the brain does not heal properly. We study the immunology of traumatic brain injuries (TBI) as well as cerebrovascular injuries and identify therapeutics that impede acute damage and promote functional repair. Because healthy vasculature is a crucial component of CNS function, we explore and discover immunological mechanisms that promote vascular repair in the damaged brain and meninges. We also study environmental variables like infections that alter repair trajectories after CNS injuries. We use many contemporary approaches, such as intravital two-photon laser scanning microscopy (TPM), to study the neural-immune interface under states of health and disease. TPM allows us to film immune cells in the living brain and meninges. We watch the dynamics of fluorescently tagged innate (e.g., microglia, monocytes, macrophages, neutrophils, dendritic cells, innate lymphoid cells) and adaptive (e.g., microbe specific CD8+ T cells, CD4+ T cells, B cells) immune cells in the CNS under steady state or in response to perturbations like infections or injuries. We also test therapeutic compounds by administering them transcranially (through the skull bone) and then visualize in real-time how these therapeutics locally influence the inflammatory process. This powerful approach allows us to evaluate the efficacy of potential therapeutics at the site of disease. In the field of infectious disease research, we have made some exciting discoveries over the past year. The CNS is covered and protected by an immunologically active assembly of membranes referred to as the meninges. The outer most layer (the dura mater) contains large venous sinuses that drain blood from the brain. These vessels are fenestrated and contain slow moving blood rendering the underlying brain susceptible to infection. However, we discovered that the dural venous sinuses are defended by resident gut-derived IgA+ plasma cells. These cells, normally found in the gut and skin, line the dural sinuses under steady state conditions, releasing anti-microbial antibodies into the lumen of the sinuses. These antibodies entrap blood-derived microbes and prevent them from entering the CNS. However, when these sinus IgA+ plasma cells are specifically depleted, we observed that a normally controlled infection like Candida albicans (a fungus) was able to enter the brain parenchyma and cause a fatal encephalitis. These data showcase the importance of resident humoral immunity in defending specialized blood-draining structures within the meninges. We have also made some important discoveries relating to CNS injuries. Traumatic brain injuries in humans range from mild to severe and are quite diverse in nature. Our laboratory has developed a focal model of mild traumatic brain injury (mTBI), referred to as meningeal compression, that reflects one type of concussive human injury among a broad spectrum. The injury is mild, focal, and occurs beneath a closed skull. Using this model, we have defined the innate immune response to mTBI from injury inception to resolution and repair. These studies have enabled us to identify the neuroprotective immune reaction that develops in response to a single injury. Over the past year, we have explored the consequences of experiencing a second brain injury within 1 day of the initial injury. In these studies, we uncovered the structural importance of the glia limitans superficialis a CNS barrier beneath the pia mater that separates the brain parenchyma from the cerebral spinal fluid space above. Following a single mTBI, this barrier becomes damaged but is quickly resealed by microglia. This rapid innate immune response helps preserve the integrity of the underlying brain tissue. However, we found that a second injury encountered within 1 day of the first does not give microglia enough time to reset. Repeat head injury heavily damages the glia limitans superficialis, and microglia are unable to reseal the barrier, which leads to substantial cell death in the brain parenchyma. Importantly, therapeutic administration of the antioxidant, glutathione, following a second brain injury helps preserve the glia limitans superficialis and markedly reduces parenchyma cell death. Thus, antioxidant therapy has the potential to mitigate the damaging effects of brain injuries if given quickly. A second type of CNS injury under investigation in the lab is cerebrovascular damage. In humans, stroke, intracerebral damage (ICH), and TBI can all lead to vascular hemorrhaging in the brain, which is often followed by potentially life-threatening brain swelling or edema. We have discovered that this edema is caused in part by massive extravasation of innate myelomonocytic cells from the blood into the brain in response to hemorrhage, and that secondary edema can be prevented by therapeutically blocking myelomonocytic cell extravasation with a combination of anti-LFA1 and anti-VLA4 antibodies. Microglia also play an important role in the cerebrovascular injury response by rapidly projecting processes that envelop damaged blood vessels and limit the extent of leakage. Pro-angiogenic microglia later participate in vascular remodeling - a process they coordinate with classical blood monocytes. Overall, our research has informed us that the innate immune system has an essential role in repairing damaged blood vessels in the brain parenchyma and meninges following cerebrovascular injury. Importantly, the damaging effects of early myelomonocytic cell extravasation can be prevented with bolus anti-LFA1/VLA4 therapy while still allowing the reparative innate immune reaction to develop later. Cerebrovascular injuries are common in humans, but little is known about mechanisms that influence differential repair trajectories. Some patients recover and regain function following a cerebrovascular injury, whereas others have poor outcomes. One environmental factor known to promote poor clinical outcomes after head injury or stroke is infection. Infections are commonly observed in TBI and stroke patients, and most occur with a week of injury. Importantly, we recently discovered that a broad range of microbes and microbial products interfere with cerebrovascular repair in the meninges and brain parenchyma via induction of type I interferons (IFN-I). These innate cytokines are often considered an essential component of anti-microbial immunity but can deviate reparative immune programs when infections are encountered in the context of an injury. Our findings explain the poor outcomes observed in TBI and stroke patients that become infected and offer a new therapeutic target to improve recovery in some of these patients. In fact, therapeutic blockade of IFN-I restored repair in our models TBI and cerebrovascular injury.