Interferon Lambda Inhibits Herpes Simplex Virus Type I Infection of Human Astrocytes and Neurons

Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Glia (Impact Factor: 6.03). 01/2011; 59(1):58-67. DOI: 10.1002/glia.21076
Source: PubMed


Herpes simplex virus Type I (HSV-1) is a neurotropic virus that is capable of infecting not only neurons, but also microglia and astrocytes and can establish latent infection in the central nervous system (CNS). We investigated whether IFN lambda (IFN-λ), a newly identified member of IFN family, has the ability to inhibit HSV-1 infection of primary human astrocytes and neurons. Both astrocytes and neurons were found to be highly susceptible to HSV-1 infection. However, upon IFN-λ treatment, HSV-1 replication in both astrocytes and neurons was significantly suppressed, which was evidenced by the reduced expression of HSV-1 DNA and proteins. This IFN-λ-mediated action on HSV-1 could be partially neutralized by antibody to IFN-λ receptor. Investigation of the mechanisms showed that IFN-λ treatment of astrocytes and neurons resulted in the upregulation of endogenous IFN-α/β and several IFN-stimulated genes (ISGs). To block IFN-α/β receptor by a specific antibody could compromise the IFN-λ actions on HSV-1 inhibition and ISG induction. In addition, IFN-λ treatment induced the expression of IFN regulatory factors (IRFs) in astrocytes and neurons. Furthermore, IFN-λ treatment of astrocytes and neurons resulted in the suppression of suppressor of cytokine signaling 1 (SOCS-1), a key negative regulator of IFN pathway. These data suggest that IFN-λ possesses the anti-HSV-1 function by promoting Type I IFN-mediated innate antiviral immune response in the CNS cells.

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Available from: Wenzhe Ho, Aug 18, 2014
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    • "ISG15 is one of the most highly induced ISGs that modifies the function of many host proteins by ubiquitin-like conjugation, termed ISGylation, and appears to play important roles in various biological and cellular processes (Sadler and Williams 2008; Zhang and Zhang 2011). IFN-l exhibit antiviral activity against a broad range of viruses, such as the encephalomyocarditis virus, vesicular stomatitis virus, herpes simplex virus type 2 (HSV2) (Kotenko and others 2003; Sheppard and others 2003; Ank and others 2006), HSV1 (Li and others 2011), human immunodeficiency virus (Hou and others 2009), influenza A virus (IAV) ( Jewell and others 2010; Svetlikova and others 2010), and rotavirus (Pott and others 2011). It has also been shown that they block hepatitis B and hepatitis C virus replication (Robek and others 2005; Diegelmann and others 2010; Pagliaccetti and others 2010; Pagliaccetti and Robek 2010). "
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    ABSTRACT: Lambda interferons inhibit replication of many viruses, but their role in the inhibition of lymphocytic choriomeningitis virus (LCMV) infection remains unclear. In this study, we examined the antiviral effects of interferon (IFN)-λ2 and IFN-λ3 against LCMV in A549 cells. We found that IFN-λ2 is a more potent inhibitor of LCMV strain MX compared with IFN-λ3, whereas both cytokines have similar antiviral effects against an immunosuppressive variant of LCMV, clone-13. We also demonstrated that the antiviral activity of IFN-λ2 is more effective if it is delivered early rather than after establishment of a long-term infection, suggesting that virus replication is only partially responsive to the cytokine. In agreement with this observation, we showed that LCMV infection significantly reduces IFNLR1 mRNA expression in infected cells. In addition, LCMV infection, to some extent, compromises the signal transduction pathway of IFN-λ2. This implies that IFN receptors as well as their downstream signaling components could be selectively targeted either directly by LCMV proteins or indirectly by cellular factor(s) that are induced or activated by LCMV infection.
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    • "In the studies on relation of toll-like receptor 3 (TLR3) immunity inborn errors to proclivity of children to HSV-1 encephalitis, neurons, oligodendrocytes and astrocytes were suggested to provide strong, intrinsic protective anti-HSV-1 immunity in the CNS (Lafaille et al., 2012; Li et al., 2012; Wang et al., 2012; Sorgeloos et al., 2013). Recent studies have shown that cells in the CNS possess intracellular innate immunity properties, having the ability to express IFNs including IFN-λ (Li et al., 2011) and other antiviral factors which suppress and eliminate HSV-1 or HSV-2 in its target cells (Paul et al., 2007). However, the precise cellular and molecular mechanisms by which IFN-λ is regulated upon viral and/or other cellular factors remain to be determined. "
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    • "Infected astrocytes have been detected in fatal human cases of WNV encephalitis, suggesting that these cells are also targeted by WNV in vivo (van Marle et al., 2007). Various secreted factors, such as the chemokine ligand CCL5, IFN, nitrous oxide, reactive nitrogen species and exosomes, play a role in restricting infection of astrocytes by several neurotropic viruses including herpes virus, human immunodeficiency virus and Junin virus (Gómez et al., 2003; Hu et al., 2012; Li et al., 2011). Although WNV-infected astrocytes express IFN-β, CCL5 and additional chemokines (Hussmann & Fredericksen, 2014; Hussmann et al., 2013; Kumar et al., 2010), our analyses indicated that secreted factors are not involved in inhibiting WNV-MAD78 infectious particle production (Fig. 1) (Hussmann et al., 2013). "
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