Research Project
2687086
Viral infection of the central nervous system (CNS) has been associated with or hypothesized as the cause of several chronic mental disorders. Examples of such mental health disorders include chronic fatigue syndrome and schizophrenia. Accumulating evidence suggests that the human immunodeficiency virus (HIV) causes cognitive impairments frequently observed in AIDS patients. More data is needed to understand the changes in the CNS environment which results from viral infection, and contributes to neuronal disorders. The long term objective of the proposed research is to generate biological, biochemical and molecular data which will promote understanding of how the brain influences, and is influenced, by neural- immune interactions during viral infection of the brain. Within this framework, two distinct phases of the neural-immune process will be examined: (1) Analysis of the process of viral antigen presentation in the CNS by non-neuronal cells; (2) Recruitment of immune cell (T lymphocytes) to regions of viral infection. Central to the proposed research plan is a biologically relevant paradigm of viral infection of the brain, which utilizes a neurotropic virus, herpes simplex virus type-1 (HSV-1); and an in vitro system, in which HSV-1 infection of trigeminal nerve explants mimics the in vivo process. Infection of immunocomponent and immunodeficient mice with two strains of HSV-1 will be used to study neural-immune interactions which occur during the establishment of an asymptomatic latent infection (strain F), and during a lethal viral infection (strain KOS). CNS tissue from infected mice will be examined for the presence of recruited T- lymphocytes, induction of MHC class I and II antigen expression, and viral spread by immunohistochemical detection of the corresponding antigens. Detailed analysis will be done employing neurobiological, immunological, and virological methodologies including (1) confocal microscopic examination of the cellular localization of viral and cellular proteins in the antigen presenting cells (APC) of the brain, (2) expressly designed bone marrow chimera mice will be used to definitely determine the primary APC in the brain, (3) fluorescence activated cell sorting (FACS) analysis of lymphocytes recruited to the brain will be used to establish lymphocyte activation status. Data accumulated from these studies will provide the groundwork to pursue our long term goal; investigation of the effector mechanisms of recruited immune cells in the CNS. In turn, this knowledge will help elucidate the role of the immune system in defending the nervous system against virus infections and the contribution of viral infection to chronic neural disorders.
