Program Director/Principal Investigator (Last, First, Middle): De La Torre, Juan C. 1R01 AI075298-01A2 Viruses can induce a variety of disease states in the central nervous system. Meningitis is a potentially fatal disorder induced by a long list of human pathogens, including viruses, and is often associated with symptoms that include fever, headache, stiffness of the neck, and seizures. Presently, very little can be done for patients with viral meningitis other than to relieve symptoms. We propose that a detailed understanding of this pathogenic process in real time may foster the development of novel interventions to alleviate symptoms and prevent permanent neurological dysfunction and fatalities. To accomplish this goal we propose to study the well-described meningitis induced by lymphocytic choriomeningitis virus (LCMV), a noncytopathic mouse as well as human pathogen. Intracerebral inoculation of mice with LCMV results in a fatal meningitis within 6 days that is mediated almost entirely by cytotoxic lymphocytes (CTL). Importantly, this disease can be completely prevented by prior vaccination or immunization. The dynamics of cellular interactions in the meninges during failed or effective control of infection have not been studied previously. Moreover, the precise mechanisms that mediate fatal injury in this model are not entirely understood. We will utilize a combination of state-of-the art viral reverse genetics, fluorescently-tagged immune cells, and two-photon laser scanning microscopy in combination with in situ staining for different molecular species to follow the local immune cell dynamics in the LCMV-infected mouse cerebral cortex and meningeal space. Our hypothesis is that CTL damage to astrocyte networks in the CNS leads to generalized fatal seizure during acute LCMV-induced meningitis, and that rapid responsiveness and the use of alternative effector mechanisms by activated memory T cells in vaccinated mice results in limited damage to astrocyte networks, maintenance of the blood brain barrier, and survival. This hypothesis will be addressed by the two focused following specific aims: 1) Completion of the first real time analyses of interactions between CTL and CNS targets infected by fluorescently-tagged LCMV, and 2) in vivo evaluation of immunological synapse formation and molecular mechanisms involved in CNS CTL targeting and damage.

Public Health Relevance

Meningitis is a disease state in humans initiated by infection of the lining of the brain (or meninges). A considerable number of human viruses can induce this disease state and the symptoms include fever, headache, stiffness of the neck, and seizures. While many viral infections are purged from the meninges without incident, an inflammatory reaction in this sensitive brain region can sometimes result in long term neurological disability or even fatalities. Presently, little is known about the immune mechanisms that mediate injury to the meninges following viral infection. Thus, the proposed study will conduct the first intravital analyses to visualize and dissect the inflammatory reaction on the surface of the virally infected brain in real time. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075298-02
Application #
7860314
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Repik, Patricia M
Project Start
2009-06-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$459,450
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Emonet, Sebastien F; Garidou, Lucile; McGavern, Dorian B et al. (2009) Generation of recombinant lymphocytic choriomeningitis viruses with trisegmented genomes stably expressing two additional genes of interest. Proc Natl Acad Sci U S A 106:3473-8
Kang, Silvia S; McGavern, Dorian B (2009) Inflammation on the mind: visualizing immunity in the central nervous system. Curr Top Microbiol Immunol 334:227-63