Viruses can enter the central nervous system (CNS) via the olfactory neuroepithelium. With one such virus, vesicular stomatitis virus, infection can result in lethal encephalitis or in the host's ability to activate both innate and acquired immune responses and clear the infection. Viral infections of the CNS occur in an immunologically privileged site. Further, neurons, which do not normally express major histocompatibility antigens, cannot be recognized by T lymphocytes performing immune surveillance for viral antigens. Viral replication can modify cellular metabolism, sometimes leading to initiation of apoptosis, resulting in the death of that cell. Infections in the CNS can directly or indirectly, through parenchymal cell products, alter the microenvironment. The new gene expression can be beneficial in alerting the innate and acquired immune system or can be pathologic, triggering physiological changes in CNS systems such as the permeability of the blood brain barrier (BBB). In this renewal application, the aims are: 1) the signals important for recruitment of inflammatory cells (sequentially NK, macrophages, and T cells) to the olfactory bulb, the site of infection, 2) the mechanisms by which VSV infection alters the BBB, and 3) further examination of the roles of distinct isotypes of NOS in mice infected with VSV. This work builds on previous studies on the recovery-promoting benefit of IL-12 administration and the mechanism of cytokine-mediated antiviral activities in neurons, funded by the application being renewed. The proposed studies will be carried out using molecular biological approaches (rt-PCR, RNAse protection, in situ hybridization), immunohistochemistry, knockout strains of mice, and drug treatment specific for enzyme systems to be explored such as production of leukotrienes and activation of C5a. Potentially important biological molecules, which will be investigated include IL-12, chemokines, prostaglandins, leukotrienes, vascular endothelial growth factor, and complement C5a. This work has both basic and clinical applications, as viral encephalitis and pathological changes in the BBB are important medical problems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC003536-07S1
Application #
6839877
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Davis, Barry
Project Start
1997-05-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
7
Fiscal Year
2004
Total Cost
$27,907
Indirect Cost
Name
New York University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Reiss, Carol Shoshkes (2010) Cannabinoids and Viral Infections. Pharmaceuticals (Basel) 3:1873-1886
D'agostino, Paul M; Amenta, Jessica J; Reiss, Carol Shoshkes (2009) IFN-beta-induced alteration of VSV protein phosphorylation in neuronal cells. Viral Immunol 22:353-69
D'Agostino, Paul M; Yang, Jingjun; Reiss, Carol Shoshkes (2009) DISTINCT MECHANISMS OF INHIBITION OF VSV REPLICATION IN NEURONS MEDIATED BY TYPE I AND TYPE II IFN. Virus Rev Res 14:20-29
Herrera, R Antonio; Oved, Joseph H; Reiss, Carol Shoshkes (2008) Disruption of IFN-gamma- mediated antiviral activity in neurons: the role of cannabinoids. Viral Immunol 21:141-52
Yang, Jingjun; Dennison, Natalie Nicole; Reiss, Carol Shoshkes (2008) PIN: a novel protein involved in IFN-gamma accumulation of NOS-1 in neurons. DNA Cell Biol 27:9-17
Trottier, Mark D; Lyles, Douglas S; Reiss, Carol Shoshkes (2007) Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection. J Neurovirol 13:433-45
Yang, Jingjun; Tugal, Derin; Reiss, Carol Shoshkes (2006) The role of the proteasome-ubiquitin pathway in regulation of the IFN-gamma mediated anti-VSV response in neurons. J Neuroimmunol 181:34-45
Ireland, Derek D C; Reiss, Carol Shoshkes (2006) Gene expression contributing to recruitment of circulating cells in response to vesicular stomatitis virus infection of the CNS. Viral Immunol 19:536-45
Ireland, Derek D C; Palian, Beth M; Reiss, Carol Shoshkes (2005) Interleukin (IL)-12 receptor beta1 or IL-12 receptor beta 2 deficiency in mice indicates that IL-12 and IL-23 are not essential for host recovery from viral encephalitis. Viral Immunol 18:397-402
Trottier Jr, Mark D; Palian, Beth M; Shoshkes Reiss, Carol (2005) VSV replication in neurons is inhibited by type I IFN at multiple stages of infection. Virology 333:215-25

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