Mechanisms Underlying Clearance of Persistent Infections and Tumors

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

We are interested understanding scenarios that result in chronic CNS immune responses, such as those observed during aging, neurodegeneration, persistent infection, and autoimmunity. These immune responses can foster deterioration of CNS barriers, leading to a decline in neurological function. Pathogens are well-established drivers of chronic CNS immune responses. For example, pathogens like human immunodeficiency virus (HIV) cause major health problems worldwide and are difficult to clear once persistence is established. It is therefore important to develop and mechanistically understand therapeutic strategies that eradicate CNS pathogens without causing unwanted immunopathology. We model states of persistent infection in the laboratory by using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Infection with LCMV clone 13 initiates a state of persistence that shares some important features with HIV-1 and other persistent human pathogens, including impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of CNS viral persistence. We have also recently discovered that this virus rapidly infects CNS barrier structures, including the meningeal sinuses, which triggers a massive local immune reaction. How CNS barriers mount a sustained immune reaction against persistent viruses is a major focus of the laboratory. We are also interested in how pathogen persistence influences CNS barrier homeostasis and the maintenance of neurological function. Another focus of our infectious disease research is on how tissues like the CNS return to homeostasis after a pathogen is cleared. We discovered that resolution of viral infection in the meninges is associated with peripheral immune cell engraftment. Under steady state, the meninges are inhabited by long-lived tissue resident macrophages. Upon viral infection, we observed that the meninges become heavily infiltrated by peripheral monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. These cells possess functional properties that are different than those of resident meningeal macrophages, including a loss of bacterial and immunoregulatory sensors. These data demonstrate that even clearance of an infection can imprint a CNS barrier like the meninges with new functional properties and alter its ability to respond to future challenges. Conceptually, this finding adds a new level of complexity to our understanding of how diseases or alterations in homeostasis might develop after a pathogen is cleared. Because the failures in adaptive immune responses to persistent infections resemble those encountered when tumors develop, our laboratory studies tumor immunology to determine why the CNS mounts such a poor immune response to glioblastomas (GBM). These rapidly growing tumors are uniformly fatal and impose considerable challenges on the brain resident and peripheral immune systems. We have observed that the glioblastoma microenvironment is largely silent in terms of adaptive anti-tumor immunity and instead supports an innate wound healing program that more closely resembles the response to brain injuries. To overcome this immunological silence, we have recently developed transcranial therapeutic approaches to enhance the meningeal immune response against GBM. We have discovered specialized niches in the meninges capable of supporting local humoral immunity and have leveraged these responses against GBM to promote tumor control. Our findings offer the possibility of controlling GBM by modulating local immune responses along immunologically active CNS barriers.