Sindbis virus (SV) is an alphavirus that infects neurons and causes acute encephalomyelitis in mice. Outcome is age-dependent and newborn mice develop fatal disease while weanling mice develop a well- characterized immune response that leads to recovery from infection and provides a model system for studying the mechanisms by which virus is cleared from neurons. Mice with severe combined immunodeficiency (SCID) do not develop an SV-specific humoral or cellular immune response and cannot clear virus. We have shown that infectious virus can be cleared from the central nervous system (CMS)by antibody (Ab) to the SV E2 glycoprotein and can be cleared from spinal cord motor neurons, but not cortical or hippocampal neurons by interferon (IFN)y. Both of these processes of SV clearance involve mechanisms that do not damage infected neurons. Ab-mediated control of intracellular virus replication is independent of complement and leukocytes and requires cross-linking of the E2 glycoprotein on the surface of the infected cell. Down-regulation of SV replication is associated with improved Na+K+ATPase-dependent cation flux, inhibition of virus budding, restoration of host protein synthesis and response to IFN-o/p. IFN-D-mediated clearance is associated with transient increases in viral RNA and protein synthesis with a decreased ratio of genomic to subgenomic RNA, recovery of cellular protein synthesis followed by reduced viral protein synthesis and inhibition of viral RNA transcription. Noncytolytic mechanisms for virus clearance result in persistence of viral RNA in the CNS. During the past granting period we have shown that both age- dependent susceptibility and noncytolytic clearance can be modeled with neuronal cell lines differentiated in vitro. In the current application we propose to determine the mechanisms of age-dependent susceptibility and of immune-mediated control of intracellular virus replication through the following specific aims: (1)To determine why mature neurons are more resistant to SV infection than immature neurons;(2)To determine what steps of virus replication are restricted in mature neurons compared to immature neurons;(3) To determine the mechanism by which IFN-D clears virus from mature neurons;and (4) To determine the mechanism by which anti-E2 antibody clears virus from mature neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038932-09
Application #
7992397
Study Section
Virology - B Study Section (VIRB)
Program Officer
Wong, May
Project Start
2001-07-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
9
Fiscal Year
2011
Total Cost
$351,575
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Nilaratanakul, Voraphoj; Chen, Jie; Tran, Oanh et al. (2018) Germ Line IgM Is Sufficient, but Not Required, for Antibody-Mediated Alphavirus Clearance from the Central Nervous System. J Virol 92:
Randall, Richard E; Griffin, Diane E (2017) Within host RNA virus persistence: mechanisms and consequences. Curr Opin Virol 23:35-42
Baxter, Victoria K; Glowinski, Rebecca; Braxton, Alicia M et al. (2017) Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis. Virology 508:134-149
Baxter, Victoria K; Griffin, Diane E (2016) Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis. J Gen Virol 97:2908-2925
Griffin, Diane E (2016) Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage. Neurotherapeutics 13:455-60
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Schultz, Kimberly L W; Vernon, Patty S; Griffin, Diane E (2015) Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7. J Virol 89:48-60
Bogerd, Hal P; Skalsky, Rebecca L; Kennedy, Edward M et al. (2014) Replication of many human viruses is refractory to inhibition by endogenous cellular microRNAs. J Virol 88:8065-76

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