The role of IFN-γ in immune responses to viral infections of the central nervous system

Cytokine & Growth Factor Reviews 13 (2002) 441–454

Survey

The role of IFN-␥ in immune responses to viral infections of the central nervous system David A. Chesler a , Carol Shoshkes Reiss a,b,c,d,∗ a

Department of Biology, New York University, 1009 Main Building, 100 Washington Square East, New York, NY 10003, USA Center for Neural Science, New York University, 1009 Main Building, 100 Washington Square East, New York, NY 10003, USA c Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Ave, New York, NY 10016, USA d Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA b

Abstract Interferon (IFN)-␥, is not only a marker of TH 1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-␥, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-␥ in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-␥ in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-␥ signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Interferon-␥; Neuron; Virus; Antiviral; Nitric oxide

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Molecular biology of IFN-␥ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. IFN-␥ expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. IFN-␥ receptor expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. IFN-␥ intracellular signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Nitric oxide synthase (NOS) and nitric oxide (NO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Interferon-␥ initiated antiviral responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. RNAseL/2 -5 OAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. PKR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. NOS and NO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Undefined and poorly characterized interferon-γ -mediated antiviral responses . . . . . . . . . . . . . .

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Abbreviations: 2 -5 OAS, 2 -5 -oligoadenylate synthetase; 2-AP, 2-aminopurine; 7-NI, 7-nitroindazole; C/EBP-␤, CCAAT/enhancer-binding protein-␤; CD, cluster of differentiation; CMV, cytomegalovirus; CNS, central nervous system; CREB, cAMP/Ca2+ response element-binding protein; CIITA, class II transactivator; dsRNA, double-stranded RNA; EAE, experimental autoimmune encephalomyelitis; eIF2␣, eukaryotic initiation factor-2␣; GAS, ␥-activation sequence; GATE, ␥-IFN-activated transcriptional element; GFAP, glial fibrillary acidic protein; GTPase, guanine triphosphate nuclease; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; IP-10, interferon-inducible protein of 10 kDa; IRF, interferon regulatory factor; JAK, Janus kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MS, multiple sclerosis; MV, measles virus; NK, natural killer; NO, nitric oxide; NOS, nitric oxide synthase; NS1, non-structural protein 1; ONOO• , peroxynitrite; PKR, dsRNA protein kinase; RNA, ribonucleic acid; RNaseL, ribonucleic acid nuclease L; SSPE, subacute sclerosing panencephalitis; STAT, signal transducer and activation of transcription; TH 1, type 1 helper cell; TNF-␣, tumor necrosis factor-␣; viperin, virus inhibitory protein, endoplasmic reticulum associated, interferon-inducible; VSV, vesicular stomatitis virus ∗ Corresponding author. Tel.: +1-212-998-8269; fax: +1-212-995-4015. E-mail address: [email protected] (C.S. Reiss). 1359-6101/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 1 3 5 9 - 6 1 0 1 ( 0 2 ) 0 0 0 4 4 - 8

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5. Viral infections in the CNS and the effects of IFN-γ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Vesicular stomatitis virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Measles virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Herpes simplex virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction During viral infections in the periphery as well as in the CNS, the goal of the host immune response is to prevent virus replication and, failing that, to eliminate virus-infected cells. In the periphery, this is accomplished mainly through the targeted destruction of virally infected cells by NK cells, CD8+ T-cells, and CD4+ T-cells and much later, the production of neutralizing antibody [1]. Because of the fundamental danger to the host of destruction of non-renewing neurons, non-cytolytic mechanisms which eliminate virus are critical for CNS infections [2,3].

2. Molecular biology of IFN-␥ 2.1. IFN-γ expression The IFN family of pro-inflammatory cytokines, first described 30 years ago because of their antiviral properties [4,5], are categorized into two distinct groups based primarily on their protein sequences, cellular sources, and use of distinct receptors. Type I IFNs, IFN-␣, -␤, and -␻, are expressed by both leukocytes and fibroblasts largely as a direct result of viral infection [6]. While IFN-␣ and -␤ are found across many species including humans and mice, IFN-␻ expression is restricted to humans [6]. An additional type I IFN, IFN-␶, was identified in ruminants. Rather than possessing antiviral properties, IFN-␶ acts as an early signal in ruminant pregnancy [7–11]. In contrast, type II family of IFNs, contains a single member, IFN-␥ [12,13]. IFN-␥ is a biologically active non-covalently linked 34 kDa homodimer secreted primarily by NK) cells, TH 1 CD4+ T-cells, and CD8+ T-cells. IFN-␥ mediates a wide range of immunomodulatory effects on both innate and acquired immunity [12]. IFN-␥ has been shown to upregulate major histocompatibility complex (MHC)-I and -II expression, activate macrophages/microglia in an antigen-specific fashion, act as a cytostatic agent on numerous normal and oncogenic cell lines, and induce several IFN-inducible antiviral mechanisms [12]. Although IFN-␥ expression within the CNS has been traditionally attributed to infiltrating NK cells and CD4+ T-cells, reports from the literature indicate that there may be endogenous sources of expression. Of particular interest are reports of an IFN-␥-like product produced by neu-

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rons [14–17]. These studies identified a 60 kDa unglycosylated protein termed neuronal-IFN-␥ (N-IFN-␥) by its cross-reactivity with several antibodies specific for IFN-␥ [14,15,17,18]. Purified N-IFN-␥ was found to have bioactivity similar to recombinant IFN-␥ including MHC-I and -II induction on macrophages and potent proliferative stimulation of the intracellular pathogen Trypanosoma brucei brucei [17]. N-IFN-␥ is expressed in IFN-␥−/− mice and is induced during VSV encephalitis (Hodges and Reiss, New York University). 2.2. IFN-γ receptor expression The IFN-␥ receptor (IFN-␥R) is composed of two subunits, an ␣ (IFN-␥R1 or IFN-␥R␣) and ␤ chain (IFN-␥R2 or IFN-␥R␤), that oligomerize into a heterotetramer consisting of two ␣ and two ␤ chains upon binding of its ligand [12]. While the IFN-␥R has been previously considered to be ubiquitously expressed on all nucleated cells with constitutive levels of the IFN-␥R␣ and regulated expression of the IFN-␥R␤ [12], Robertson et al. [19] have revealed a restricted pattern of IFN-␥R immunoreactivity in the CNS. In examining IFN-␥R expression in neuronal processes, and therefore, regions where IFN-␥ could affect neurons directly, their study found constitutive expression of IFN-␥R in the normal rat brain is limited primarily to the olfactory bulb, limbic system, hypothalamic structures, and brain stem [19]; though in contrast to other studies [20,21], Robertson et al. [19] failed to find IFN-␥R expression in glial components. Using the upregulation of Fos expression as marker for IFN-␥-mediated activation, intracerebral injection resulted in increased Fos immunoreactivity predominantly in areas co-localizing with IFN-␥R expression. It would appear based on the neuronal distribution of IFN-␥R expression and IFN-␥-mediated induction of Fos in the CNS that IFN-␥ serves to play a role early in the immune response to limit the spread of an intracellular pathogen such as a virus. 2.3. IFN-γ intracellular signaling IFN-␥ signal transduction is made up of primary and secondary responses. STAT1 [12], mediates the primary signaling response. After ligand engagement of the IFN-␥R, STAT1 is phosphorylated by JAK1 and JAK2, dimerizes, and subsequently translocates to the nucleus where it

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Fig. 1. IFN-␥ receptor and intracellular signaling cascade. Cytokine-binding induces the formation of the heterotetrameric receptor complex, activating the JAK/STAT kinase cascade ultimately regulating gene expression in the nucleus.

induces transcription of a subset of IFN-␥-inducible genes (Fig. 1). Included in that subset of genes are additional transcription factors such as interferon regulatory factor (IRF)-1 and class II transactivator (CIITA), which are responsible for mediating secondary IFN-␥ responses including the upregulation of MHC-I and -II, expression of the chemokine interferon-inducible protein of 10 kDa (IP-10), and antiviral mechanisms [22]. Ancillary signaling pathways have also been described for IFN-␥. IFN-␥ has been found to induce the phosphorylation of p42/p44 MAPK (ERK1/2) through Jak1 and Raf [23]; activation of Raf leads to cytoskeletal plasticity, frequently seen as morphological changes in IFN-treated cells. In addition, IFN-␥ has been found to regulate inducible genes such as p48/IRF-9 through a novel cis-acting promoter element termed the ␥-IFN-activated transcriptional element (GATE) [24,25] by the CCAAT/enhancer-binding protein-␤ (C/EBP-␤) [24–26]. The large majority of IFN-␥-inducible responses are attributed to STAT1-dependent mechanisms though recent reports have demonstrated a number of STAT1-independent responses. A subset of IFN-␥-inducible genes are regulated in the absence of STAT1. In some of these instances, gene regulation is identical in WT and STAT1−/− cells though interestingly in others, STAT1 was found to be a repressor of gene expression [26–28].

3. Nitric oxide synthase (NOS) and nitric oxide (NO) Nitric oxide (NO) is a small, reactive, highly diffusible gas which is important in many aspects of physiology and antiviral responses [29,30]. NO is formed by the NOS-mediated conversion of l-arginine to l-citrulline (Fig. 2). Three isoforms of NOS encoded by distinct genes have been identified. All three isoforms possess interaction domains for calmodulin, NADPH, flavin adenine dinucleotide, flavin mononucleotides, and an N-terminal heme site [30]. Table 1 provides a brief summary of the properties of the three NOS isoforms. The neuronal isoform (nNOS, bNOS, NOS-1) is constitutively expressed. It exists as a cytosolic homodimer and its activity is dependent on calcium and calmodulin [31]. Though it is constitutively expressed, its expression level can be modulated under many circumstances including in response to cytokine treatment [32] and following ischemic/reperfusion injury [33]. NOS-1 expression throughout the CNS is involved in many physiologic processes including long-term potentiation [34–36], nocioception [37,38], and neurotransmitter release [39]. NOS-2 (macNOS, iNOS) is not expressed constitutively but is rapidly induced by IFN-␥, TNF-␣, IL-12, and LPS. Like NOS-1, it exists as a cytosolic heterodimer [31] but in contrast to NOS-1, is Ca2+ -independent and found constitu-

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Fig. 2. Synthesis of nitric oxide from l-arginine and the production of reactive by-products. NOS catalyzes the conversion of l-arginine to NO and l-citrulline. NO acts through subsequent reactions to form reactive by-products. Table 1 NOS isoform properties and expression profiles in the CNS Isoform

CNS expression

Regulation and activity

NOS-1 (nNOS or bNOS)

Neurons

NOS-2 (macNOS or iNOS)

Microglia, astrocytes, macrophages

NOS-3 (eNOS)

Endothelium, astrocytes, neurons

Ca2+ -dependent, constitutively expressed and stimuli modulated (IFN-␥, IL-12, TNF-␣, Ca2+ ), low capacity for NO production Ca2+ -independent, non-constitutively expressed; inducible by IL-12, IFN-␥, TNF-␣, LPS and others; high capacity for NO production Ca2+ -dependent, constitutively expressed and stimuli modulated by cytokines and estrogens, low capacity for NO production

tively associated with calmodulin [31]. Its CNS expression is restricted to microglia and astrocytes along with infiltrating, inflammatory macrophages [40–43]. NOS-2 has the capacity to produce large bursts of NO that greatly exceed the amount produced by either of the two other NOS isoforms [44,45]. The endothelial isoform of NOS (NOS-3, eNOS) like NOS-1, is constitutively expressed and calcium and calmodulin dependent. It is expressed by most endothelial cells and a subset of neurons in the CNS [46]. Astrocytes also have the capacity to express NOS-3 [47]. NOS-3-dependent production of NO has been shown to have a central role in the regulation of blood pressure [48]. NO participates in numerous, complex biological activities, the best known of which is its ability to induce the relaxation of vascular smooth muscle cells [49]. NO has the ability to interact both directly with targets and indirectly through the formation of reactive intermediates. The free radical, NO• , can directly nitrosylate thiol groups of cysteine residues leading to numerous products. Under biologically relevant conditions, NO can react with molecular oxygen (O2 ), superoxide anions (O2 − ), and transition metals to form reactive nitrogen species (NOx ), highly reactive peroxynitrite (ONOO• ), and metal adducts, respectively. Through direct action, or the formation of these reactive intermediates, NO is involved in a wide range of biologic activities both normal and pathologic. NO has been demonstrated to be a key component of host defenses against pathogens including bacteria, fungi, viruses, and protozoan

parasites [29,50–54]. Excessive production of NO has been associated with disease pathology in amyolaterotrophic sclerosis (ALS) [55], Huntington’s chorea, Alzheimer’s disease and cerebral ischemia [56]. NO has also been implicated as a contributor to pathology in multiple sclerosis though this finding is still controversial [57].

4. Interferon-␥ initiated antiviral responses Work published previously by the Reiss laboratory has shown that IFN-␥ treatment can reduce viral titers in infected neuronal cells in vitro by up to 100-fold compared with untreated cells demonstrating its potent antiviral activity [32]. This effect is not restricted solely to VSV but can be demonstrated in CNS infections with other viruses including Sindbis virus, polio virus, influenza virus [32,58], and measles virus (MV) [15,59]. In the case of other viruses such as herpes simplex virus type 1 (HSV-1), IFN-␥ has been shown to limit transynaptic transmission [60], prevent viral reactivation [61], and inhibit virally induced apoptosis [62]. The literature on the role of IFN-␥ and IFN-␥R in viral infection is summarized in Table 2. Several IFN-␥ regulated antiviral mechanisms have been defined and described. In mice the most prominent mechanisms include Mx, ribonucleic acid nuclease (RNase)L, 2 -5 -oligoadenylate synthetase (2 -5 OAS), double-stranded (ds)RNA protein kinase (PKR), and NOS [63–66]. Important in considering the contribution and effectiveness of these

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Table 2 Consequences of IFN-␥ and IFN-␥R deficiencies on viral infections of the CNS Virus

IFN-␥−/−

IFN-␥R−/−

HSV

Increased morbidity and mortality compared with WT [61,62,172–174]

VSV

No differences compared with WT [176] (Hodges and Chen, New York University) Increased morbidity and mortality [15,59] No differences compared with WT [177,178] Increased susceptibility to infection [180]

Increased morbidity and mortality compared with both WT and IFN-␥−/− [61,173], increased complications in patients with IFN-␥R−/− immunodeficiency [175] No differences compared with WT (Hodges, Chen, and Reiss, New York University). – Increased susceptibility to infection compared with WT [179] No initial difference compared to WT though increased late pathology [181]

Measles virus LCMV Theiler’s murine encephalitis virus

Table 3 IFN-␥-induced antiviral mechanisms Antiviral protein

Mechanism of action

Susceptible viruses

Mx RNaseL/2 -5 OAS

Inhibition of transcription of viral RNA Synthesis of oligoadenylate chains by 2 -5 OAS in response to dsRNA which activates RNaseL to degrade ssRNAs halting virus replication Phosphorylation of eIF2␣ in response to dsRNA resulting in inhibition of protein synthesis Targeted nitrosylation of cysteine and tyrosine residues and/or disruption of sulfhydryl-bonds in viral proteins

Measles [15,166]; influenza [182,183]; VSV [184] ECMV [185]; HIV [186]; vaccinia virus [187]

PKR NOS

ECMV [188]; HIV [189]; VSV? [190,191] VSV [149]; HSV-1 [149]; HIV [192]; EBV [193]; Coxsackie [194]; vaccinia [158]

different antiviral mechanisms in the IFN response is that none of them act ubiquitously. Specifically, the contribution of IFN-mediated antiviral responses, is pathogen-specific (Table 3). What might be effective against one virus will not necessarily have similar or comparable effects against another. This is not surprising considering the range of DNA and RNA virus-host cell replication patterns involved as well as viral evasion proteins.

a hallmark of many viral infections [72–77]. 2 -5 OAS synthesizes oligoadenylate chains in response to dsRNA binding acting as an activator of RNaseL. Binding of dsRNA by 2 -5 OAS in turn activates RNaseL to target and degrade single-stranded RNA species inhibiting viral replication [78]. This effect is exemplified during infections with encephalomyocarditis virus (ECMV) [79], HIV [80], and vaccinia virus [81].

4.1. Mx

4.3. PKR

Mx proteins are IFN-inducible, large GTPases belonging to the dynamin superfamily [63]. Depending on the species, they are localized to either the cytosol or nucleus [67]. The antiviral action of Mx proteins varies greatly depending on the virus being investigated. For example, the murine Mx1 protein is a nuclear localized protein that efficiently inhibits the replication of influenza A and other members of the orthomyxovirus family by blocking primary transcription [68,69]. In contrast, the human MxA protein also inhibits Influenza A replication though at a later stage in the replicative cycle [69]. Mx has also been demonstrated to inhibit VSV replication at the transcriptional level in both human and murine models [70,71]. The known genes encoding Mx proteins are absent in most commonly used laboratory mouse strains such as BALB/c, B6 and C3H, but is present in the A2G strain [64].

Perhaps one of the best-studied antiviral enzymes, PKR, an interferon-inducible serine/threonine kinase, is ubiquitously expressed. Activated by autophosphorylation in the presence of dsRNA, PKR exerts its antiviral effects primarily through the phosphorylation of one its many target substrates, the ␣-subunit of the eukaryotic initiation factor 2␣ (eIF2␣) [66]. This phosphorylation leads to the sequestration of eIF2B and the global inhibition of protein synthesis [66]. PKR has been demonstrated in vitro to be important in the inhibition of encephalomyocarditis virus [82], HIV [83], and VSV replication [84–87]. Highlighting the importance of PKR is the evolution of IFN evasion mechanisms in a wide range of viruses that are aimed at circumventing PKR action. The influenza A protein, NS1, interacts with PKR to prevent its activation and action [88]. In hepatitis C virus infections, similar effects are found; the NS5A and the E2 protein have been implicated as inhibitors of PKR [89,90]. Vaccinia virus has also developed a mechanism for the inhibition of PKR through the virally encoded E3L and K3L proteins [73,91]. Deletion of the E3L protein results IFN susceptibility during

4.2. RNAseL/2 -5 OAS Expression of RNaseL and 2 -5 OAS is regulated by IFN-␥ and activated in response to the presence of dsRNA,

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vaccinia virus infection [92]. A PKR-antagonistic function has not been attributed to any of the gene products encoded by VSV. 4.4. NOS and NO NOS and its product, NO, and its reaction product, ONOO− , have been implicated as important antiviral mechanisms for a wide range of viruses. NO has been found to be an effective antiviral molecule in studies using DNA and RNA viruses belonging to the Picornaviridae, Flaviviridae, Coronaviridae, Rhabdoviridae, Reoviridae, Retroviridae, Parvoviridae, Herpesviridae, and Poxviridae families demonstrating its broad spectrum of effectiveness [54,93]. Several mechanisms have been proposed for the antiviral properties of NO. The predominant mechanism underlying the antiviral properties of NO is the nitrosylation of viral proteins during infection [93–95]. NO chemically modifies cysteine and tyrosine residues presumably disrupting protein function either through the impairment of folding and/or the disruption of sulfhydryl-bonds within the protein. Nitrosylation by ONOO• does not appear to be random but rather to target-specific viral proteins. In Coxsackie virus infection, a member of Picornaviridae, nitrosylation of catalytic residues in its two cysteine proteases leads to the interruption of its life cycle [96–98]. Similar effects have been attributed to the nitrosylation of the HIV-1 aspartyl protease [99]. The reverse transcriptase of HIV-1 has also been identified as a target of NO action [100]. Putative targets of NO action have also been identified in vaccinia virus [101], ectromelia virus [102], Epstein-Barr virus [98], VSV [103], and HSV-1 [104]. 4.5. Undefined and poorly characterized interferon-γ -mediated antiviral responses Though a substantial body of research exists characterizing the roles and contributions of the IFN-mediated antiviral responses described above, a number of recent studies have hinted at additional, previously unidentified mechanisms of inhibition. A systematic examination of the known IFN induced antiviral mediators (Mx, PKR, RNAseL, and NO) during murine cytomegalovirus (CMV) infection of bone marrow macrophages revealed one such mechanism [105]. IFN-␥ has been found to inhibit early events in the replication of murine CMV demonstrated by the reduction in immediate early (IE) gene expression [106]. These results demonstrated that IFN-␥ is able to inhibit the replication of murine CMV and IE gene expression through a cis-acting, IFN-␥R- and STAT1-dependent mechanism that was independent of PKR, RNAseL, Mx and NO. Using triply-deficient (PKR−/− , RNAseL−/− , Mx−/− ) mice and primary dendritic cell cultures, Ryman et al. [107] found that the IFN-inducible antiviral response to Sindbis virus infection was left largely intact.

One protein, recently implicated as an IFN-inducible protein, is vig1/cig5 or viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon-inducible) [108,109]. Boudinot et al. [108] demonstrated the induction of vig1/cig5 during VSV and pseudorabies virus infection of murine dendritic cells. VSV infection caused the direct induction of cig5, in contrast to pseudorabies virus infection, which required an intact IFN response for induction. Evidence for the antiviral properties of cig5 came from the studies of Chin and Cresswell [109] in which over-expression of the viperin protein inhibited the productive infection of fibroblasts with human CMV. It is unclear how viperin may act to inhibit viral replication but the observation of its close association with the endoplasmic reticulum and Golgi complex suggest it might function through impeding the trafficking of viral proteins during replication.

5. Viral infections in the CNS and the effects of IFN-␥ While a growing knowledge of the mechanisms through which CNS infections are dealt with immunologically, a greater appreciation for the consequences of viral infections in the CNS is evolving. A large number of laboratories are focusing their research on both the inflammatory mediators involved in immune responses to, and the consequences of viral infections within the CNS. Attention has been directed to measles virus, which rarely can produce subacute sclerosing panencephalitis (SSPE), a frequently fatal syndrome characterized by chronic inflammation, deterioration of intellectual capacity and motor degeneration [110,111]. Through the infection and super activation of microglia, HIV infection has been found to cause AIDS associated dementia in about a third of HIV patients [112–114]. Borna virus infection has also been associated with behavioral and cognitive disruption in rats although this still remains controversial in human disease [115,116]. In addition to damage done to the CNS as a direct consequence of CNS infections, several investigators have worked to establish causal links between viral infections and autoimmune disease in the CNS using model systems. Semliki forest virus and Theiler’s murine encephalomyelitis virus have been studied extensively as viral inducers of experimental autoimmune encephalomyelitis, a murine model for the study of multiple sclerosis [117–120]. In spite of the fact no direct causal link has yet been shown between viral infections and multiple sclerosis, many experimental findings point in this direction (for recent reviews on viruses in autoimmune disease, see [121,122]). 5.1. Vesicular stomatitis virus The main focus of the research performed in our laboratory is to understand and characterize immune responses in the CNS during acute viral encephalitis. To accomplish

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this, the vesicular stomatitis virus (VSV) is being used. VSV, is an enveloped, negative-sense, single-stranded RNA virus belonging to the family Rhabdoviridae [123]. The genome of VSV encodes five proteins: a variable glycoprotein, a matrix protein, a nucleoprotein, a large protein, and two phosphoproteins in overlapping reading frames [123]. Two principle serotypes have been identified for VSV: New Jersey and Indiana [124]. Cows and horses are the major natural hosts of VSV, and it is transmitted primarily through arthropod vectors such as the sandfly. In its natural host, infection is mild, characterized by vesicular lesions in the oral cavity. A wide range of studies have been carried out using VSV as a model system including: viral assembly [125], endogenous antigen presentation by MHC-II [126], viral entry [127], membrane fusion [128], defective interfering viral particles [129,130], viral immunity [131,132], and viral inhibition by interferons [32]. Intranasal instillation with VSV has been shown to lead to lethal infection of the CNS [133], which has allowed its use as a model for studies of neurotropic viral infection [131,134–140]. Intranasal infection of mice with VSV results in the initial infection of the olfactory neuro-epithelium [141]. Within 12–24 h, the virus is transmitted to neurons within the olfactory bulb, and the infection spreads caudally through the CNS ultimately reaching the spinal cord [131,135,137]. During infection, the respiratory epithelium is spared and virus cannot be isolated from nearby peripheral neurons such as the trigeminal ganglion [141]. Mice surviving the infection completely clear the virus from the CNS by day 12 post-infection [131]. We have found that infection with VSV activates and requires both innate and acquired immune responses. In characterizing the contribution of T-cell-mediated mechanisms, antibody depletion of CD4+ or CD8+ was found to increase severity of infection compared with control animals [136]. Infection of athymic (nu/nu) mice demonstrated 10-fold greater viral titers and increased rates of mortality compared to their euthymic littermates [136]. In addition, BALB/c-H-2dm2 (dm2) mice, which lack the MHC-I restricting H-2Ld molecule, were found to mount an effective CD4+ antiviral response [131,142]. The dm2 mice were more resistant to viral challenge than BALB/c control mice indicating that CD4+ T-cells are sufficient for a response to VSV infection. Characterization of kinetics of the immune response to VSV demonstrated an absence of B-cells within the CNS until after the infection was cleared [138–140,143]. While antibody production contributes to immunity against re-challenge with VSV, it is unlikely to be important in control of the initial infection. Furthermore, we have established that TH 1-like responses, characterized by the production and action of cytokines such as IL-12 and IFN-␥, are advantageous to host recovery [144] (for a review of the role of IL-12 in VSV encephalitis, see [145]). Current work in our laboratory is aimed at understanding the role of IFN-␥ during viral infection and eluci-

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dating the mechanisms through which IFN-␥ establishes an antiviral state against VSV infection in neurons. In neuroblastoma cells and primary neurons, we have found that IFN-␥ can rapidly induce cellular changes resulting in a significant inhibition of VSV replication. Though IFN-␥ is a potent inducer of an antiviral response in this system, it is not a requirement for host-survival. Mice deficient in either IFN-␥ or IFN-␥R are equally susceptible to VSV encephalitis as their syngenic wild-type controls illustrating the redundancy of the inflammatory immune response [146] (Hodges, Chen, and Reiss, New York University). Both in vitro and in vivo, shown through the use of specific NOS-1 inhibitors such as 7-nitroindazole (7-NI), a selective NOS-1 inhibitor [32,147], and NOS-1-deficient animals, NO-mediated antiviral effects are central to the clearance of VSV infection in the CNS [32,140]. This presents an interesting finding because of the limited capacity for NO production by NOS-1. In contrast to the inducible isoform of NOS (NOS-2), which can produce ␮M quantities of NO [45], NOS-1 is capable of only producing nM amounts of NO [148], generally held to be insufficient in immune responses. What appears to allow for this antiviral effect is the upregulation of NOS-1 expression following IFN-␥ treatment (data not shown). The increases in NOS-1 expression observed correlate closely with increases in NO production and increased inhibition of VSV replication (data not shown) [149]. The question remains of how IFN-␥ is able to effect these changes. Increasing intervals of IFN-␥ treatment result in greater inhibition of VSV replication. This effect correlates well with the observed increases in NOS-1 protein expression. Protein synthesis experiments demonstrate that short periods of IFN-␥ exposure induce changes in NOS-1 synthesis and increase the stability of the NOS-1 protein. Accordingly, short intervals of IFN-␥ are sufficient to establish an antiviral state. IFN-␥ signaling can be divided into primary and secondary events. Initial signaling from the IFN-␥ receptor takes place through Janus kinases and STAT1 [22,150]. Activated STAT1 can in turn translocate to the nucleus resulting in the transcription of IFN-inducible genes including secondary signaling components such as the IRF-1, which is itself a transcription factor [151]. In addition, IFN-␥ has been shown to activate ERK1/2 through a Jak1-dependent mechanism and C/EBP-␤ [25,26,152,153]. As previously described in a number of cell types, IFN-␥ signaling in neurons also occurs through the phosphorylation of STAT1 and/or ERK along with the induction of IRF-1 (unpublished observation). Sequence analysis of available murine NOS-1 promoter sequences has revealed several putative GAS and IRF-1-binding sequences. This suggests that IFN regulation of NOS-1 and ultimately the antiviral state against VSV would be dependent on the transcriptional regulation of NOS-1 (Fig. 3) [154,155]. Unlike the majority of genes known to be IFN-␥-inducible, NOS-1 is regulated post-transcriptionally through increases in both protein synthesis and stability (data not shown). Two possibilities are

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Fig. 3. Putative IRF-1 and STAT-binding sites in the NOS1 promoter. Structure of NOS-1 exons 1a and 1b and sequence 5 . Genbank Accession #AF135825. Using the MatInspector Software Package [154], a putative IRF-1-binding site (GAAAAATGAGAGC) was identified at −2078 → −2066 and a putative STAT half-site (TTTCCAGAA) at −368 → −360. Above the gene schematic is a scale identifying the locations of features of interest based upon the submitted GENBANK sequence.

readily presented by this finding. On the one hand, this could indicate a novel mechanism for IFN-␥-mediated gene regulation suggesting the action of undefined signaling pathways in neurons. On the other hand, this might indicate that there is a missing component to the observed response. An intermediate induced by IFN-␥ may in turn act to regulate the increased expression of NOS-1. Kinetics studies unfortunately do not clarify the situation. Rapid changes in neurons caused by IFN-␥ induces the synthesis of NOS-1 as well as the observed antiviral effect. Supporting the latter hypothesis, is in vitro evidence using STAT1−/− primary neurons, demonstrating a requirement for STAT1 in the IFN-␥-mediated antiviral response to VSV infection. 5.2. Measles virus Measles virus, a paramyxovirus, is considered in most cases, a relatively harmless childhood disease preventable by proper and timely vaccination. In very rare cases however, MV can gain access to the CNS resulting in a range of severe neurologic complications. Among these complications are acute disseminated encephalomyelitis, a monophasic autoimmune disease with immune responses against myelin basic protein similar to that documented in mice with experimental autoimmune encephalomyelitis [156], measles inclusion body encephalitis (MIBE), and SSPE [157,158]. Both MIBE and SSPE are progressive diseases due to persistent CNS infection, neither of which is currently treatable or curable. Though, a large body of literature exists characterizing the clinical findings and significance of the neurologic complications of MV infection, little is known about the immune response to CNS MV infection. Clinical observations indicate that T-cell-mediated immunity is crucial in patients recovering from acute infection. Both CD4+ and CD8+ T-cell clones recognizing MV epitopes can be isolated from patients [159,160]. Furthermore, individuals with suppressed

T-cell function are more susceptible to complications [161]. Studies in murine models of MV infection of the CNS using mouse adapted MV strains, or more recently using human CD46 (the co-receptor for MV) transgenic mice, have shown a requirement in vivo for CD4+ but not CD8+ T-cells in clearance of MV from infected neurons, a result similar to that found with VSV infection [59,162,163]. Unlike VSV infection however, IFN-␥ is required in mice to control and clear MV from infected neurons. BALB/c mice treated with an anti-IFN-␥ neutralizing antibody are more susceptible to MV encephalitis compared with controls [59]. Furthermore, human CD46+ transgenic mice deficient in IFN-␥ (IFN-␥−/− ) show similar results with significant increases in morbidity and mortality compared with IFN-␥-competent CD46+ controls [15]. The mechanisms through which MV replication is inhibited are not clear although evidence indicates a requirement for MxA in the IFN-␥-induced antiviral response in mice [164–166]. 5.3. Herpes simplex virus HSV-1 and -2 are large DNA viruses both of which are highly prevalent in the human population. Whereas initial infection with HSV-1 principally occurs in early childhood, HSV-2 infection is primarily spread through sexual contact. In contrast to both MV and VSV infection which are characterized as being acute infections (the exception being persistent MV infection leading to disorders such as SSPE); HSV infection is a life-long state in which latency is established in ganglia following an initial acute disease. In both childhood and adult HSV infection disease is characterized by recurrences or outbreaks which resolve in a timely manner but have little risk of mortality due to the focused nature of the infection. Neonatal infection with HSV, on the other hand, is almost always symptomatic and frequently lethal. The lethality of neonatal infection is attributed to encephalitis or disseminated infection involving multiple

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organ systems including the CNS [167,168]. With few exceptions, patients surviving neonatal HSV encephalitis demonstrate severe neurologic deficits [169]. IFN-␥ has the ability to affect HSV infected neurons in a number of ways. In vitro replication of HSV-1 in neuroblastoma cells is inhibited by IFN-␥ through a nitric oxide-independent mechanism [32]. Mice expressing IFN-␥ through a rhodopsin promoter driven transgene are less susceptible to lethal HSV-1 encephalitis despite an increase in inflammation due to the expression of IFN-␥ [170,171]. The demonstrated increase in survival in IFN-␥ transgenic mice was suggested to be due in part to an upregulation of the anti-apoptotic gene, Bcl2, which promoted cell survival compared to HSV infected wild-type animals [62]. Consistent results were found in IFN-␥−/− mice exhibiting greater numbers of apoptotic neurons and decreased levels of Bcl2 expression [172]. IFN-␥ has also been implicated in having a role in limiting the axonal transmission of HSV from infected neurons to epidermal cells [60] and importantly, IFN-␥ has been found to inhibit the reactivation of latent HSV in the trigeminal ganglion [5,61].

6. Conclusions IFN-␥ is critical for antiviral responses not only in the periphery, but also in the CNS. The mechanisms of action are tailored to the infection and range from Mx in myxovirus (influenza) infections to PKR in hepatitis C virus infection to induction of NOS for VSV and Coxsackie virus infections. HSV-1 latency may also be maintained in the presence of IFN-␥. In the CNS, especially with respect to infections of neurons (which are non-renewable), non-cytolytic effector mechanisms which eliminate intracellular viruses are essential to preserve neuron function. IFN-␥, as well as inflammatory cytokines (IL-12 and TNF-␣) elicit the innate antiviral responses in neurons. We have shown in neurons both in vitro and in vivo, the signaling and regulation of NOS-1 by IFN-␥ and its role in VSV encephalitis in this review.

Acknowledgements We would like to thank Jane McCutcheon (New York College of Dentistry), Adolfo Garc´ıa-Sastre, Jan Vilcek and David Levy (Mt. Sinai NYU Medical Center) for their helpful comments, feedback, and technical assistance. Funding was provided by NS39746 and DC03536 to CSR. References [1] Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: the immune system in health and disease. New York: Garland; 1999. [2] Guidotti LG, Chisari FV. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 2001;19:65–91.

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