The central nervous system (CMS) poses a unique challenge to the immune system, as it is considered an immunologically specialized compartment that resides behind a non-fenestrated barrier and significantly limits the expression of antigen-presenting machinery. Because the CNS is compartmentalized and imposes strict regulatory mechanisms on the adaptive immune system, a multitude of pathogens that infect humans (e.g. HIV, herpes virus, measles virus, HTLV-1, JC virus, etc.) are capable of establishing persistence in the CNS. These persistent infections can give rise to severe behavioral alterations and neurological dysfunction, which adversely affects human health. Persistent infections that gain access to the CNS often do so by first establishing persistence in the periphery. This common scenario consequently presents biomedical researchers with the challenge of eradicating the pathogen from both the periphery as well as the CNS. Given that the CNS provides such a favorable environment to viruses seeking persistence, we postulate that achieving clearance from this specialized compartment will be far more challenging than from peripheral tissues. The proposed study will explore a murine model system in which an immunosuppressive virus is introduced through a peripheral route and then establishes prolonged persistence in the CNS despite the eventual clearance from the periphery. Clearance from the periphery coincides with a functional reactivation of virus-specific T cells (a scenario we hope to achieve in humans), yet this response is unable to prevent prolonged viral persistence within the CNS. Importantly, administration of exogenous memory T lymphocytes at the peak of CNS viral infection results in efficient clearance of the virus from both the periphery and the CNS. Thus, an adoptively transferred population of memory T lymphocytes can achieve successful clearance despite an inadequate endogenous immune response. The proposed study is designed to significantly advance our understanding of T cell immunity to persistent viral infections in the CNS by establishing the shortcomings of the endogenous T cell response (Specific Aim#1) and the modus operand of a highly successful adoptive response (Specific Aim#2). The main objective of this research is mechanistically define the factors that give rise to successful CNS viral clearance so that we are better able to supplement a failing (or inadequate) endogenous response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070967-05
Application #
8026029
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2007-03-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2011
Total Cost
$455,501
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oldstone, Michael B A; Edelmann, Kurt H; McGavern, Dorian B et al. (2012) Molecular anatomy and number of antigen specific CD8 T cells required to cause type 1 diabetes. PLoS Pathog 8:e1003044
Popkin, Daniel L; Teijaro, John R; Lee, Andrew M et al. (2011) Expanded potential for recombinant trisegmented lymphocytic choriomeningitis viruses: protein production, antibody production, and in vivo assessment of biological function of genes of interest. J Virol 85:7928-32
Saphire, Erica Ollmann; Oldstone, Michael B A (2011) Measles virus fusion shifts into gear. Nat Struct Mol Biol 18:115-6
Ward, Simone V; George, Cyril X; Welch, Megan J et al. (2011) RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci U S A 108:331-6
Popkin, Daniel L; Teijaro, John R; Sullivan, Brian M et al. (2011) Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner. Cell Host Microbe 9:212-22
Lee, Andrew M; Paulsson, Johan F; Cruite, Justin et al. (2011) Extraneural manifestations of prion infection in GPI-anchorless transgenic mice. Virology 411:1-8
Ng, Cherie T; Sullivan, Brian M; Oldstone, Michael B A (2011) The role of dendritic cells in viral persistence. Curr Opin Virol 1:160-6
Oldstone, Michael B A; Campbell, Kevin P (2011) Decoding arenavirus pathogenesis: essential roles for alpha-dystroglycan-virus interactions and the immune response. Virology 411:170-9
Garidou, Lucile; Heydari, Sara; Truong, Phi et al. (2009) Therapeutic memory T cells require costimulation for effective clearance of a persistent viral infection. J Virol 83:8905-15
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

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