PROJECT 1 Viral infections targeting glia and neurons commonly cause encephalitis and have high mortality. Long term neurological dysfunction potentially resulting from altered cell function in persistently infected cells or immune pathology are common. Type I interferons (IFNa/(3) provide the first line of host defense against viral spread to and within the CNS. However, little is known about the ability of resident CNS cells to mount innate responses during acute or persistent CNS infections. This proposal addresses how distinct IFNa/p responses in microglia, astrocytes and oligodendrocytes contribute to pathogenesis following infection with a non lethal, demyelinating neurotropic coronavirus. Despite the concerted efforts of IFNa/p and adaptive immune cells to prevent mortality, virus is incompletely cleared, resulting in viral RNA persistence in the CNS. The overall hypothesis tested is that narrowly focused innate signals by oligodendrocytes constitute a protective mechanism for their survival and function in maintaining myelin, at the cost of persistent infection. Induction of IFNa/p by microglia and/or astrocytes is critical to induce an antiviral state in an autocrine and paracrine fashion.
Aim # 1 will establish whether CNS cell types with highly specialized function, e.g. oligodendrocytes, rely on other cell types to signal the presence of invading pathogens. A dependence of IFNa/p signaling by individual cell types for protection will be confirmed by conditional abrogation of IFNa/p signaling in oligodendrocytes, astrocytes and microglia.
Aim #2 will analyze mechanisms of RNAseL mediated protection against virus induced demyelination. It is based on novel findings of significantly enhanced demyelination and mortality of virus infected RNAseL deficient mice, despite effective viral control.
Aim #3 will reveal whether persistently infected oligodendrocytes are immunologically silent, or trigger sufficient innate responses to directly or indirectly sustain local inflammation and demyelination. The overall approaches rely on a combination of RNA expression analysis in glial populations isolated directly from the infected CNS, immunohistochemical analysis, and chimeric mice to distinguish between innate affects on resident versus infiltrating cells. By defining mechanisms of innate immune regulation within the CNS during both acute and persistent infection, these studies will benefit our understanding and manipulation of factors critical for both anti viral function and amelioration of pathology manifested by demvelination.

Public Health Relevance

. Using no more than two or ttiree sentences, describe tlie relevance of tills research to public health. In this section, be succinct and use plain language that can be understood by a general, lay audience. DO NOT EXCEED THE SPACE PROVIDED. Interferons are USed therapeutically;however, little is know about the responses of individual cell types within the CNS. This proposal will define the innate responses of distinct glial cells during acute viral encephalitis providing novel insights into potential therapies. The role of innate components in regulating protection of the CNS will be defined as well as testing of new potential therapeutic approaches to modify demyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS064932-05
Application #
8535835
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$302,702
Indirect Cost
$109,899
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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de Aquino, Maria Teresa P; Kapil, Parul; Hinton, David R et al. (2014) IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination. J Immunol 193:285-94
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Kapil, Parul; Stohlman, Stephen A; Hinton, David R et al. (2014) PKR mediated regulation of inflammation and IL-10 during viral encephalomyelitis. J Neuroimmunol 270:1-12
Savarin, Carine; Bergmann, Cornelia C; Hinton, David R et al. (2013) MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis. ASN Neuro 5:e00127
Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54
de Aquino, Maria Teresa P; Puntambekar, Shweta S; Savarin, Carine et al. (2013) Role of CD25(+) CD4(+) T cells in acute and persistent coronavirus infection of the central nervous system. Virology 447:112-20
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382-92
Phares, Timothy W; Stohlman, Stephen A; Hwang, Mihyun et al. (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416-27

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