Neurons can be infected by viruses, potentially leading to propagation and spread of the virus within the central nervous system, cell death and encephalitis. Unlike peripheral cells which may be infected with viruses, the immune system has developed cell-sparing mechanisms of eliminating virus growth. These studies are directed at understanding host cytokine responses which regulate the replication of virus in neurons. In this competing renewal, Aims 1 and 2 are focused on the sensitization of neurons by type 1 interferon (IFN-beta). We will determine the cellular pathways which are activated and are able to effect an inhibitory role on the viral life cycle of vesicular stomatitis virus (VSV); preliminary data show that these are distinct from that used by IFN-gamma. In most cell types, RNA viruses readily induce the production of IFN-beta during their replication, which includes double stranded RNA intermediates. However, in our preliminary studies, VSV is an exception, and no IFN-beta was detected during infection both in vivo and in vitro. We will characterize the means by which VSV prevents neuronal synthesis of IFN-beta which could protect neighboring cells. We will determine the mechanism of peripheral induction of IFN-beta gene expression at 24h post intranasal infection, and examine the role of Toll Like Receptors (TLR) in the responses both of neurons and of splenocytes; we will determine if PDC are responsible for IFN-beta synthesis.
Aim 3 will continue our studies on the antiviral effector which is induced by type 2 IFN (IFN-gamma) nitric oxide (NO); we have shown that mRNA for NOS-1, the neuronal isoform of nitric oxide synthase, does not change in cells treated with IFN-gamma, but the amount of the enzyme increases as does its activity. Studies are designed to define the novel mechanism of the increase in the enzyme which is induced by treatment of neurons with IFN-gamma.
In aim 4, we will elucidate the mechanism by which this small molecule, NO, is able to inhibit viral protein synthesis and release of infectious virions from neurons. These studies are important because the insights gained will be beneficial in developing new and novel treatments for viral encephalitis considered new and emerging infections. They elucidate previously unsuspected interactions between the immune system and the central nervous system.
| Tsvetkov, Andrey S; Arrasate, Montserrat; Barmada, Sami et al. (2013) Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol 9:586-92 |
| Tsvetkov, Andrey S; Ando, D Michael; Finkbeiner, Steven (2013) Longitudinal imaging and analysis of neurons expressing polyglutamine-expanded proteins. Methods Mol Biol 1017:1-20 |
| Sharma, Punita; Ando, D Michael; Daub, Aaron et al. (2012) High-throughput screening in primary neurons. Methods Enzymol 506:331-60 |
| Sarojini, Sreeja; Theofanis, Thana; Reiss, Carol Shoshkes (2011) Interferon-induced tetherin restricts vesicular stomatitis virus release in neurons. DNA Cell Biol 30:965-74 |
| Reiss, Carol Shoshkes (2010) Cannabinoids and Viral Infections. Pharmaceuticals (Basel) 3:1873-1886 |
| D'Agostino, Paul M; Reiss, Carol Shoshkes (2010) A confocal and electron microscopic comparison of interferon beta-induced changes in vesicular stomatitis virus infection of neuroblastoma and nonneuronal cells. DNA Cell Biol 29:103-20 |
| Tsvetkov, Andrey S; Miller, Jason; Arrasate, Montserrat et al. (2010) A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A 107:16982-7 |
| Miller, James M; Bidula, Sarah McNulty; Jensen, Troels Mygind et al. (2010) Vesicular stomatitis virus modified with single chain IL-23 exhibits oncolytic activity against tumor cells in vitro and in vivo. Int J Interferon Cytokine Mediat Res 2010:63-72 |
| 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 |
| Miller, James; Bidula, Sarah M; Jensen, Troels M et al. (2009) Cytokine-modified VSV is attenuated for neural pathology, but is both highly immunogenic and oncolytic. Int J Interferon Cytokine Mediat Res 1:15-32 |
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