As the most abundant glial cells population within the central nervous system (CNS), astrocytes play an important role in the CNS inflammatory reactions. However, there is emerging evidence that astrocytes participate in the CNS innate immunity, as they display an array of receptors involved in innate immunity. Astrocytes express certain members of the Toll-like receptors (TLR) family, in particular, TLR3, a major trigger of innate immune response to viral infections. In addition, astrocytes functionally express retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity. Our early studies demonstrated that the activation of TLR3 in astrocytes inhibited HSV replication. We also showed that TLR3 signaling of macrophages suppress HIV replication. However, it is unclear about the role of TLR3/RIG-I signaling of astrocytes in the neuroprotection and CNS innate immunity against HIV. Also, there is little information about whether opioids impair the antiviral function of astrocytes. The overall aim of this project is to determine the anti-HIV activity and neuroprotective effect of TLR3 and RIG-I activation of astrocytes and the impact of opioids on astroglial TLR3/RIG-I signaling. We hypothesize that the astroglial TLR3/RIG-I signaling can mount an effective immunity against HIV and protect neuronal cells. Furthermore, we hypothesize that morphine compromises astrocyte-mediated antiviral immunity and facilitates HIV infection of microglia. We propose two specific aims to address these hypotheses:
Aim 1 Determine the effect of astroglial TLR3/RIG-I signaling on HIV infection of microglia (glia-glia interaction) and the impact of morphine on this astrocyte-mediated anti-HIV action.
Aim 2 Determine the effect of astroglial TLR3/RIG-I signaling on the neuronal cell protection in the context of morphine use and/or HIV. These proposed studies should for the first time provide insight of the beneficial role of astroglia TLR3/RIG- I signaling in the neuronal cell protection ad the CNS innate immunity against HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA036163-02
Application #
8664359
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Sorensen, Roger
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Liu, Jin-Biao; Zhou, Li; Wang, Yi-Zhong et al. (2016) Neuroprotective Activity of (-)-Epigallocatechin Gallate against Lipopolysaccharide-Mediated Cytotoxicity. J Immunol Res 2016:4962351
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2016) (-)-Epigallocatechin-3-Gallate Enhances Hepatitis C Virus Double-Stranded RNA Intermediates-Triggered Innate Immune Responses in Hepatocytes. Sci Rep 6:21595
Li, Jie-Liang; Zhuang, Ke; Wu, Guang-Yao et al. (2015) Magnetic resonance imaging study of a simian/human immunodeficiency virus-infected Chinese rhesus macaque with HIV-associated dementia. AIDS Res Hum Retroviruses 31:272-3
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2015) Comparison of antiviral activity of lambda-interferons against HIV replication in macrophages. J Interferon Cytokine Res 35:213-21
Dai, Ming; Wang, Xu; Li, Jie-Liang et al. (2015) Activation of TLR3/interferon signaling pathway by bluetongue virus results in HIV inhibition in macrophages. FASEB J 29:4978-88
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2014) Hepatitis C virus impairs TLR3 signaling and inhibits IFN-? 1 expression in human hepatoma cell line. Innate Immun 20:3-11
Mastrogiannis, Dimitrios S; Wang, Xu; Dai, Min et al. (2014) Alcohol enhances HIV infection of cord blood monocyte-derived macrophages. Curr HIV Res 12:301-8
Sang, Ming; Liu, Jin-Biao; Dai, Ming et al. (2014) Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques. Antiviral Res 112:103-12
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2013) Hepatic stellate cells, liver innate immunity, and hepatitis C virus. J Gastroenterol Hepatol 28 Suppl 1:112-5
Zhou, Yu; Bao, Rong; Haigwood, Nancy L et al. (2013) SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans. Retrovirology 10:89