key: cord-0040882-x3oyp4w5
authors: Reiss, Carol Shoshkes
title: Innate Immunity in Viral Encephalitis
date: 2016-04-08
journal: Neurotropic Viral Infections
DOI: 10.1007/978-3-319-33189-8_8
sha: ee08db213ffc7b665ea6a5d44d2d121a5701f5a0
doc_id: 40882
cord_uid: x3oyp4w5

Innate immune responses to pathogens are evolutionarily ancient and are found in the most primitive organisms. These are highly conserved and are not pathogen-specific, but are in response to classes of molecular structures. Infections can be perceived both extracellularly and intracellularly by Pathogen Associated Molecular Patterns (PAMPs) and their host cell ligands, Pathogen Recognition Receptors (PRRs), among them, Toll-Like Receptors (TLRs). The innate immune response to infection includes the release of soluble preformed mediators, or synthesis of cytoplasmic enzymes, cytokines, chemokines, interferons (IFNs), lipid mediators, proteins of the complement cascade, neurotransmitters, nucleotides, and components of transcription factors (High Mobility Group B1, receptors for sex hormones/steroids). Directed cellular migration of parenchymal astrocytes and microglia, as well as recruitment across the blood brain barrier (BBB) of circulating neutrophils, natural killer, monocytes, macrophages, dendritic cells, and ultimately T lymphocytes to the site of infection are also hallmarks of innate responses to infections. These responding cells contribute their own secreted effector molecules and effector activities (such as phagocytosis). Distinct viruses are capable of infecting every cell type (endothelial cells, ependymal cells, perivascular macrophages and pericytes, astrocytes, microglia, oligodendrocytes, Schwann cells, and neurons) in the central nervous system (CNS). These CNS infections challenge the host with a different set of problems than do peripheral viral infections. Among the complications are (a) neurons that rarely express Class I or Class II Major Histocompatibility Complex (MHC) molecules and are thus not suitable targets for either CD4(+) or CD8(+) MHC-restricted T cells, (b) an enclosed volume that is constrained from swelling during inflammation, as well as poorly developed lymphatic drainage, and (c) the immunologic privilege of the CNS which leads to extremely limited immune surveillance for pathogens. Therefore, the role of innate immunity, both from CNS-resident cells and their products, and from circulating inflammatory cells and molecules which traverse the BBB are essential to “buy time,” inhibiting viral replication and dissemination, until the host can marshal an adaptive immune response. The immune responses are crucial for host survival from the infection. Consequently, successful pathogens, especially those that persist, have developed a wide variety of evasive approaches to limit the inhibition of replication. Many of these pathways are highlighted in individual chapters that precede this one. These evasive measures range from neutralizing host secreted molecules (cytokines and chemokines) with soluble receptors, encoding anti-inflammatory proteins in their genome, preventing signal transduction, blocking inhibition of protein synthesis, degradation of essential antiviral molecules, preventing apoptosis, and blockade of the nuclear pore complex. In this chapter, I will attempt to cover the breadth of the innate immune response to viral infection, but will also devote more space to generally under-considered aspects than to the well-known components. There are some caveats to consider, as most experiments have been performed in the murine model and not in man; further, conclusions from experiments using in vitro cultured cells (whether primary or established lines) may not reflect physiological conditions in an undisturbed CNS. Lastly, we now appreciate the complexities imposed on hosts by polymorphisms in genes of critical pathways, leading to increased susceptibility or resistance of that individual but not others.

Semliki Forest virus (SFV), Sindbis, Theiler's murine encephalomyelitis virus (TMEV), and West Nile virus (WNV) Fadnis et al. 2013 ; Nazmi et al. 2014 ; Cuevas and Ross 2014 ; Denizot et al. 2012 ; El-Hage et al. 2011 ; Furr and Marriott 2012 ; McKimmie et al. 2005 ; Neal 2014 ; Olson and Miller 2004 ; Sabouri et al. 2014 ; Szretter et al. 2009 ; Taylor et al. 2014 ; Thomas et al. 2014 ; Wollish et al. 2013 ; Zhou et al. 2008 ; Zolini et al. 2014 ) .

TLR signaling may regulate the expression of micro-RNAs including MiR-146 and MiR-155, leading to down-regulation of some infl ammatory genes (Aalaeiandabili and Rezaei 2013 ). MiR-155 may regulate JEV-induced infl ammation by controlling Src Homology 2-containing inositol phosphatase-1 (SHIP-1) (Thounaojam et al. 2014b ) and MiR-29b targets TNF-α-induced protein 3 (Thounaojam et al. 2014a ). However, enhanced production of MiR-155 may lead to BBB dysregulation (Lopez-Ramirez et al. 2014 ) .

RIG-I binds 5′ uncapped single stranded RNA, an essential intermediate in RNA virus replication (Goubau et al. 2014 ; Hornung et al. 2006 ) . MDA5 , in contrast, recognizes dsRNA (Wu et al. 2013 ) , and is required for picornavirus responses . Like TLRs, RIG-I activation leads to activation of a protein variously known as Cardif/IPS-1/MAVS/VISA upstream of IRF3 and NF-kB activation, which transduce the signals with nuclear translocation, leading to the production IFN-β and all the downstream IFN-stimulated genes (ISGs) . RIG-I is negatively regulated by a deubiquitinase, USP21 .

While these pathways have been well documented in many cell types, they may not always "work" in the CNS. For instance, while Vesicular stomatitis virus (VSV) replication is extremely sensitive to the antiviral effect of pretreatment of neurons with IFN-β, VSV infection of dendritic cells rapidly induces IFN, it fails to elicit IFN-β production in neurons (Trottier et al. 2005 ) . The mechanism(s) by which IFNs alter cellular physiology to resist viral infection is distinct in neurons when compared to cell types that have been more frequently studied (D'Agostino et al. 2009a , b ; Chesler et al. 2003 ) . VSV also evades cell-autonomous responses through one of many actions of the viral M protein, essentially preventing mRNA export from the nucleus (Faria et al. 2005 ) . In mice, VSV infection elicits IFN-β production by plasmacytoid dendritic cells in peripheral lymphoid compartments (Akira and Hemmi 2003 ) , no detectable IFN-β is made in the CNS during the fi rst week of VSV encephalitis (Trottier et al. 2007 ). In contrast, both Theiler's encephalomyelitis virus (TMEV) and LaCrosse virus infections led neurons to produce Type I IFN (Delhaye et al. 2006 ) . Both RIG-I and MDA5 are essential to detect and control WNV infection (Carty et al. 2014 ; Errett et al. 2013 ) .

The Receptor for Advanced Glycation End-products ( RAGE ) , an activating receptor, is expressed on many cells including vascular smooth muscle cells, endothelial cells, monocytes, and microglia (Ramasamy et al. 2005 ) . It was originally recognized as a contributor to the infl ammation seen in diabetes, and binds, as its name suggests, proteins that have been posttranslationally modifi ed with glucose. Engagement of RAGE by its ligands leads to signal transduction through NF-kB and synthesis of proinfl ammatory mediators, leading to neuroinfl ammation and oxidative stress (Tobon-Velasco et al. 2014 ) . Other ligands for the receptor are S100 family proteins, HMGB1 and insoluble complexes of Aβ peptide, which are released during tissue damage in arthritis, atherosclerosis, aging, neurodegeneration, pulmonary diseases, sepsis, and ischemia (Chuah et al. 2013 ; Kang et al. 2014 ). This has led to the classifi cation of RAGE as a Damage Associated Molecular Pattern ( DAMP ) receptor (Foell et al. 2007 ) . Thus direct or indirect compromise of neurons and parenchymal cells during viral encephalitis leads to the release of HMGB1 (Wang et al. 2006 ) or S100 that can activate microglia, perivascular macrophages, and pericytes, as well as the microvascular endothelial cells (Jaulmes et al. 2006 ; Rong et al. 2005 ). Release of S100 or HMGB1 during VSV encephalitis did not contribute to the production of IFN-β by splenic plasmacytoid dendritic cells, since infusion of soluble RAGE did not suppress the response (Reiss and Schmidt, unpublished data) . Thus, the BBB may be disrupted; cells within the CNS will secrete cytokines, chemokines, and other infl ammatory mediators. This could be among the fi rst of the sequential waves of innate immunity in response to the viral infection .

The initial report of a factor made by cells which inhibited viral replication was made ~50 years ago (Isaacs and Lindenmann 1957 ) . There are three Types of IFN . Type I is more diverse, produced by virtually all cells and includes IFN-α, IFN-β, and IFN-τ. Type II has only one member, IFN-γ; Type III comprises IL-28 and IL-29, a family of IFN-λ proteins (Reid and Charleston 2014 ; Guayasamin et al. 2014 ; Hermant and Michiels 2014 ) . IFNs inhibit viral replication by pathways described below, may also lead to neurodegeneration and demyelination through the activation of microglial production of neurotoxins (Owens et al. 2014 ; Block et al. 2007 ; Mana et al. 2006 ) .

IFN may also be a benefi cial cytokine in LCMV and Lassa fever infections where viral pathogenesis may induce vascular leak (Baccala et al. 2014 ). In Langat virus and TBE infections, IFN is protective against fatal neurotropic disease (Weber et al. 2014a ) . In measles infections, neurons express IFN needed for early control (Cavanaugh et al. 2015 ) , but in intranasal VSV infection, astrocytes are the source (Detje et al. 2015 ) . Therefore, the benefi cial and pathologic effects of IFNs may depend on the quantity and duration of expression.

Once IFNs have been induced and secreted, these cytokine bind ubiquitously expressed receptors and induce a signal transduction kinase cascade starting with Jaks and STATs, leading to nuclear translocation of phosphorylated STAT complexes that result in gene induction in virtually all cells (Nallar and Kalvakolanu 2014 ; Ivashkiv and Donlin 2014 ; Owens et al. 2014 ) . As with most other signal transduction cascades, there are regulatory phosphatases that dampen the IFNmediated induction, these include S uppressors o f c ytokine s ignaling ( SOCS ) and P rotein i nhibitor of a ctivated S TAT1 ( PIAS ) proteins. Resveratrol may upregulate SOCS-1, and thus dampen infl ammation (Dragone et al. 2014 ) . While the Jak-STAT pathway is predominant, secondary signal transduction pathways are also important for IFN's activity (Ivashkiv and Donlin 2014 ) . Although most of the consequences of IFN binding and signaling are transcriptional, not all of the inductive effects of IFNs require new mRNA production; I will discuss that below. IFN responses are essential host components of intrinsic and cell autonomous immunity to viral infection . Many viruses block IFN signaling or downstream mediators such as Tick borne fl aviviruses and IRF-1 signaling (Robertson et al. 2014 ). The exact pathways by which IFNs antagonize viral replication required are not yet fully elucidated. New techniques such as silencing are providing insights into the downstream mediators (Diamond and Farzan 2013 ; Fensterl et al. 2012 ; Schoggins et al. 2014 ) , as are explorations of specifi c genes used by some viruses to evade antiviral pathways (Taylor and Mossman 2013 ) such as HSV γ34.5 (Rosato and Leib 2014 ) or Rabies P-protein (Wiltzer et al. 2014 ) . JEV modulates SOCS in infected macrophages, inhibiting the production and release of proinfl ammatory cytokines (Kundu et al. 2013 ).

Many tumors have been shown to have disabled IFN responses; this has led to the development of several viruses for oncolysis , that is, infection to target tumors but spare normal tissue.

Expression of IFNs may be regulated by cellular micro-RNAs , targeting the IFN mRNA for destruction. MiR-548 suppresses IFN-λ1 expression (Li et al. 2013b ) and MiR-466I targets IFN-α mRNA , leading to increased viral replication.

Some IFN-stimulated genes ( ISG ) are critical for co-stimulation, antigen processing, and presentation, some for antiviral effects, others contribute to regulation of angiogenesis, cellular apoptosis, or stasis (Xiao et al. 2006 ) , and other physiological processes. Hundreds of IFN-regulated genes have been identifi ed using microarray analysis and functional assays Cho et al. 2013 ; Schoggins et al. 2014 ) . Traditionally these were studied in isolation, and many antiviral pathways have been well characterized including Mx, PKR, RNAseL, OAS, and IDO. I will focus on a few of the more important antiviral pathways controlled by IFNs.

The fi rst antiviral IFN-stimulated pathway studied in detail initially for myxovirus (Infl uenza) infections, Mx , was discovered in 1978 by Lindenmann and colleagues; they observed that some mice were spontaneously resistant to infl uenza virus replication and later showed that Mx had GTPase activity (Lindenmann et al. 1978 ; Isaacs and Lindenmann 1957 ; Kochs et al. 1998 ) . Other GTPases including Very Large Inducible GTPase-1 and TGTP/Mg21/IRG-47 are induced by IFNs (Klamp et al. 2003 ) . Guanylate binding proteins are also ISGs. These include GBP-1, a Dynamin superfamily member with GTPase activity (MacMicking 2004 ) .

MxA was induced in HIV and Simian immunodefi ciency virus (SIV) infection of the CNS (Singh et al. 2014 ; Zaritsky et al. 2012 ) , and in Reovirus infections Mx was critical to limit viral replication (Dionne et al. 2011 ) . WNV evades the antiviral activity of MxA (Hoenen et al. 2014 ). An isoform of MxA may lead to enhanced HSV-1 replication (Ku et al. 2011 ). There are polymorphisms in the promoter region of human MxA; these may lead to altered gene expression, and thus sensitivity to infections or to resistance to exogenous IFN (Tran Thi Duc et al. 2013 ) .

St imulator of I FN g enes ( STING ) [also known as m ediator of I RF3 a ctivation ( MITA) ] is activated by IF N-γ i nducible protein 16 ( IFI16 ) binding to viral dsDNA and HN200; STING then activates TANK binding kinase-1 (TBK-1) phosphorylation of the transcription factor IRF3, resulting in expression of ISGs (Thompson et al. 2014 ) . MITA/STING is an ER and mitochondrial membranebound cytoplasmic sensor for pathogen-induced cyclic dinucleotides (cyclic GMP-AMP); its C-terminal domain recruits TBK1 and IRF3 (Dubensky et al. 2013 ; Ran et al. 2014 ) . The host enzyme cyclic GMP-AMP synthase, cGAS (also called MB21D1 ), is the DNA and also dsRNA sensor (Hornung et al. 2014 ; Schoggins et al. 2014 ) . NLRC3 is a negative regulator of STING activation . Diffusion of cGAMP to neighboring cells may lead to paracrine cell-autonomous innate immunity (Ablasser et al. 2013 ) .

IFI16 senses and contributes to control of HIV-1 infection (Jakobsen et al. 2013 ) . STING can also bind to reverse transcriptase intermediates of Human T cell leukemia virus (HTLV-1), and with IRF3 and SAMHD1, activate apoptosis (Sze et al. 2013 ) . In many viral infections, there is an arms race between the host's ability to shut down viral replication and the virus inactivating host antiviral pathways; that is observed with HSV-1 ICP0 and US3-PK and STING (Kalamvoki and Roizman 2014 ) . Hepatitis C virus (HCV) NS4B blocks STING activation of TBK-1 (Ding et al. 2013 ). The Dengue virus (DENV) NS2B/3 protease cleaves STING (Aguirre et al. 2012 ; Green et al. 2014 ) .

IF N-i nduced protein with t etratricopeptide repeats ( IFIT ) family proteins contribute to antiviral responses IFIT1 (ISG56), IFIT2 (ISG54), IFIT3 (ISG60), IFIT5 (ISG58) and are regulated by viral infection (Hyde et al. 2014 ; Zhang et al. 2013b ). IFIT1 binds the 5′ capped 2′-O unmethylated RNA of JEV inhibiting its replication (Kimura et al. 2013 ), but VEE mutants evade IFIT1 (Hyde et al. 2014 ). IFIT2 protects mice from VSV neuropathogenesis (Fensterl et al. 2012 ) and VSV infection of the peripheral nervous system (Fensterl et al. 2014 ). Ifi t2 is essential for host control of neurotropic Mouse Hepatitis Virus A59 (MHV) (Butchi et al. 2014 ) , EMCV, MHV, and WNV (Fensterl and Sen 2015 ) , and HBV (Pei et al. 2014 ) . IFITM is an IFN-induced membrane associated protein. IFIT3 potentiates antiviral signaling by connecting TBK1 and MAVS . They have broad-spectrum antiviral activity (Diamond and Farzan 2013 ) . However, some neurotropic RNA viruses including WNV can evade host restriction by IFIT family members (Daffi s et al. 2010 ) .

The ISG Indoleamine 2,3-Dioxygenase ( IDO ) , a catabolic enzyme for tryptophan, generates kynurenines. IDO may have regulatory effects on T cell activity (Sakurai et al. 2002 ) and may be neuroprotective or neurotoxic: IDO contributes to alterations in serotonin metabolism, enhances astrocyte viability, but contributes to the formation of toxic quinolinic acid ).

IDO has antiviral activity against vaccinia virus, HTLV-1, measles, and HSV-1 (Adams et al. 2004 ; Maloney et al. 2000 ; Oberdorfer et al. 2003 ) . However, it may be antagonistic to containment of HIV-1 (Miller and Bhardwaj 2013 ) . IFN-induced alterations in amino acid metabolism can suppress infection, but clearly this is a two-edged sword.

Although the phosphatase(s) and kinase(s) altered by IFN-β treatment in neurons were not identifi ed, in IFN-β-treated neurons, the posttranslational modifi cation of two of the fi ve VSV proteins was profoundly altered; the M protein was hyperphosphorylated and the P protein, a subunit of the RNA-dependent RNA polymerase, was hypo -phosphorylated. M protein lost affi nity for the RNP complex, impairing assembly, and the RNA-dependent RNA polymerase activity was altered. Together, these modifi cations led to inhibition of productive VSV replication in neurons (D'Agostino et al. 2009a , b ; D'Agostino and Reiss 2010 ) .

There are many other ISGs that have antiviral activity, although they are less well studied. One of these is ISG12; it contributes to resistance to Sindbis encephalitis (Labrada et al. 2002 ) . ISG12 is a nuclear envelope protein that binds nuclear receptors like p eroxisome p roliferation a ctivating r eceptors (PPARs) (Uhrin et al. 2013 ). Cytokines and chemokines will be discussed below.

Posttranslational modifi cations of proteins are essential for their activities, their cellular localization, and also their half-life. One regulator of protein lifespan is the proteasome; proteins are targeted for degradation by addition of strings of ubiquitin ( Ub ), polyubiquitin tails, by a series of proteins that recognize the target (E1) bridge that complex (E2) to the ubiquitin ligase (E3). There are also host cellular enzymes capable of stripping Ub from proteins, deubiquitinases (Herrmann et al. 2007 ).

There are both host-cell benefi cial applications of Ub-modifi cation and pro-viral life cycle modifi cations. Malfunction of this pathway leads to accumulation of proteins that should have been degraded, and can result in neurodegenerative diseases (Atkin and Paulson 2014 ).

An example of viral-enabling modifi cation is induction of autophagy, as viruses generate membranes for their cytoplasmic replication organelles (Suhy et al. 2000 ; Nchoutmboube et al. 2013 ) . Autophagy can also be associated with presentation of viral glycoproteins to class I MHC molecules, facilitating recognition of the infected cell by CD8 cytolytic T cells (Tey and Khanna 2012 ) .

Mono-ubiquitination is often associated with either targeted proteins on the cell surface directed to the cellular endosomal sorting complexes required for transport ( ESCRT ) pathway or in viral assembly, with viral proteins usurping the ESCRT pathway to deliver viral components to the cell surface for assembly and budding; neurotropic viruses employing the vacuolar protein sorting pathway for assembly include VSV, Rabies, LCMV, Japanese encephalitis virus (JEV), HIV, HSV-1, and Epstein-Barr virus (EBV) (Votteler and Sundquist Wesley 2013 ; Chen and Lamb 2008 ) .

TRIM79α, an ISG, facilitates the ubiquitin-dependent degradation of TBE's viral polymerase but does not recognize the closely related WNV protein . As with so many other essential host antiviral pathways, viruses have devised novel evasion tools. HSV-1 and RNA viruses including VSV induce Siglec-G , that recruits SHP2 and the E3 Ub ligase c-Cbl to RIG-I, targeting RIG-I for proteolysis ). This pathway, capable of preventing IFN induction by RIG-I, can in turn be antagonized by IFN, inactivating Siglec-G .

HSV-1 ICP0 induces depletion of CD83 in dendritic cells, diminishing their effectiveness to present viral proteins to T cells (Heilingloh et al. 2014 ) . ICP0 also targets the ND10 DNA repair complex proteins hDaxx, Sp100 and PML to degradation via the Ub-ligases RNF8 and RNF168 (Lilley et al. 2011 ). Varicella zoster virus (VZV) ORF61 antagonizes IFN production by targeting IRF3 for degradation (Zhu et al. 2011 ) .

HIV-1 has two proteins that target cellular proteins for proteosomal removal: Vpu prevents CD317/tetherin from retaining nascent viral particles on the cell surface (Schmidt et al. 2011 ) , and Vif targets APOBEC3 , the cytidine deaminase .

There are two other host cell proteins that are similar to Ub and can crossregulate: ISG15 and SUMO . ISG15 has been shown to play a central role in hostcell antiviral responses in VSV, LCMV, and HSV-1 infections (Campbell and Lenschow 2013 ; Lenschow 2010 ) .

SUMO-modifi ed proteins are often found in PML nuclear bodies, where proteins may be sequestered (Lallemand-Breitenbach and de The 2010 ). IFN regulation of MiRs including the Lin28/Let-7 pathway may enhance SUMO expression and inhibition of HIV-1 and HSV-1 infections (Sahin et al. 2014a ) . IFN treatment and oxidative stress may lead to changes in Sumoylation of target proteins in the PML bodies (Sahin et al. 2014a , b ) . SUMO conjugation can also be evaded by encephalomyelocarditis virus, HSV-1, VZV, and EBV (Mattoscio et al. 2013 ) .

Tetherin/BST-2/CD317 is an unusual cell surface glycoprotein with both gpi and transmembrane domains holding the protein around lipid rafts (Billcliff et al. 2013 ) . It is expressed by many cell types including neurons, and is induced by both IFN-α/β and IFN-γ (Sarojini et al. 2011 ) . Tetherin is an ISG contributing to antiviral activity for VSV in neurons (Sarojini et al. 2011 ) .

This protein is able to dimerize and tether, hold virus particles on the surface, preventing budding and release of viruses that exit the cell via lipid rafts (Gustin and Douglas 2013 ) . This antiviral pathway is so important that many viruses have developed evasive pathways (Neil 2013 ; Sauter 2014 ) . HIV Vpu antagonizes tetherin via Ub-modifi cation and degradation, and protecting cells from antibody-dependent cell mediated cytotoxicity (ADCC) (Arias et al. 2014 ) . Glycoproteins of Filoviruses, HSV-1, Sendai, and SIV also block this pathway (Nikovics et al. 2012 ; Bampi et al. 2013 ; Zenner et al. 2013 ; Gnirss et al. 2014 ) . SIV nef and HSV-2 Env mediate endocytosis of tetherin and intracellular sequestration (Serra-Moreno and Evans 2012 ). HHV-8 K5 ubiquitinates tetherin (Mansouri et al. 2009 ). CD317/tetherin is an important host cell glycoprotein found at lipid rafts, whose expression is enhanced by IFNs, and can retain budding viruses.

The production of superoxide (O 2 *), nitric oxide (NO), and peroxynitrite (ONOO − ) contribute to elimination of many intracellular pathogens. There are three isoforms of the enzyme responsible for generating NO, nitric oxide synthase (NOS) (Bruckdorfer 2005 ) . In the CNS, NOS-1 is constitutively found in neurons, NOS-2 induced microglia and infl ammatory macrophages, and NOS-3 constitutively in astrocytes, ependymal and endothelial cells (Reiss and Komatsu 1998 ) . NO is not only involved in long-term potentiation in the CNS, it also contributes to regulation of blood fl ow (Murad 2006 ) . Astrocytes and endothelial cells release NO, resulting in dilation of capillaries and increased local perfusion (Moore 2000 ) .

NO has been associated with some infl ammatory neurological disorder (Siciliano et al. 2011 ; Banach et al. 2011 ; Bernstein et al. 2011 ) . The mechanism of NO-mediated inhibition is covalent modifi cation of viral proteins at cysteine, serine, and tyrosine, resulting in inappropriate folding, assembly, and/or enzyme activity. NO-mediated inhibition and/or pathology in the CNS contributes to the host response for Reovirus , TMEV, HIV-1, SIV, Adenovirus, Junin, Bornavirus, Venezuelan equine encephalitis (VEE), MAIDS, CMV, Murray Valley encephalitis, MHV, Sindbis, VSV, rabies, JEV, and dengue (Andrews et al. 1999 ; Brodie et al. 1997 ; Cheeran et al. 2000 ; Dietzschold and Morimoto 1997 ; Gendelman et al. 1994 ; Gomez et al. 2003 ; Goody et al. 2005 ; Hooper et al. 2001 ; Koeberle et al. 2004 ; Komatsu et al. 1999a ; Liao et al. 2012 ; de Souza et al. 2013 ; Koustova et al. 2000 ; Lane et al. 1999 ; Lin et al. 1998 ; Mestre et al. 2005 ; Minagar et al. 2002 ; Molina-Holgado et al. 1999 ; Murphy 2000 ; Navarra et al. 2004 ; Schoneboom et al. 1999 ; Thongtan et al. 2010 ) .

NOS-2 is not constitutively expressed but is rapidly induced when macrophages or microglia are exposed to infl ammatory cytokines. Microglia produce reactive oxygen species, as well, contributing to neurotoxicity block (Block et al. 2007 ). However, unlike most of the IFN-regulated effector molecules described above, NOS-1 mRNA is not induced in neurons by IFNγ and other infl ammatory cytokines , although treatment of neurons leads to accumulation of the enzyme and greater activity due to degradation of a protein inhibitor (Chesler et al. 2004a , b ; Chesler and Reiss 2002 ; Komatsu et al. 1996 ; Yang et al. 2007 Yang et al. , 2008 . This is one instance where IFN-mediated of antiviral activity is at a posttranscriptional level.

Neurons release a variety of peptides and hormones in order to "talk" to other neurons. Many of these proteins have activities outside the synaptic signaling, and can regulate immune responses. Among these molecules are Substance P, Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP/PACAP), neurokinin1 (NK1), and α-melanocyte stimulating hormone (α-MSH) (Dantzer 2004 ; Brogden et al. 2005 ; Metz-Boutigue et al. 2003 ; Prod'homme et al. 2006 ) . NK1 and NPY are infl ammatory and may have Defensin-like activity [Defensins are discussed below]. Others like VIP/PACAP are negative modulators, which act principally on dendritic cell induction of regulatory T cells (Delgado et al. 2006 ; Gonzalez-Rey et al. 2007 ). Thus, the impact of many neurotrophins, peptides, and neurotransmitters is by modulation of adaptive immune response, as has been seen with CMV and HIV-1 infection (Souza et al. 2014 ) .

Adenosine signaling, through surface A1 and A2A adenosine receptors, has been shown to be neuroprotective (Perigolo-Vicente et al. 2014 ; Latini et al. 1996 ) . The receptors also regulate pain (Sawynok and Liu 2003 ) . In HIV infection, these receptors have been shown to play an anti-infl ammatory role (Gilbert et al. 2007 ). However, A1 receptors may also contribute to neutrophil infi ltration, although this is antagonized by A2 receptors (Cronstein et al. 1992 ) . Expression of A2B receptors is induced by HIF-1-α, a cytokine-inducible transcription factor (Kong et al. 2006 ). ATP, released by cells, can attract neutrophils to tissues via engagement of A3 and P2Y2 receptors. There is reciprocal modulation of cannabinoid receptor expression by adenosine (Carrier et al. 2006 ) , thus signaling by one neurotransmitter can alter the response of neurons to other neurotransmitters. Cannabidiol was shown to be protective in infl ammation during TMEV infection via regulation of A2A receptors (Mecha et al. 2013 ) .

Cannabinoids are both endogenously synthesized (endocannabinoids) lipid neurotransmitters and are also found in some plants (e.g., marijuana) or synthetic pharmaceuticals. Two serpentine 7-transmembrane receptors have been well described: CB 1 expressed by neurons and CB 2 expressed by cells of the reticuloendothelial system including microglia (Ullrich et al. 2007 ). The functions of these receptors are distinct, although the same signaling pathways are used; the serpentine 7-transmembrane receptor is G-protein coupled. These receptors (a) negatively regulate Ca 2+ channels inhibiting Ca 2+ release, (b) activate Raf-1, MEK, and ERK, as well as (c) adenyl cyclase which ultimately activates protein kinase A. The CB 1 receptor is associated with hypothermia, immobility, euphoria, and hyperphagia, while the CB 2 receptor is a negative regulator of monocyte and microglial activation, hence immuno-dampening. Thus selective receptor agonists can target either immune responses or neurons. However, this distinction is potentially murky when you consider the regulation of cell-autonomous innate immune responses to viral infections in neurons.

Cannabinoids have been shown to be neuroprotective in Huntington's disease, Parkinson's disease, and multiple sclerosis (Pryce and Baker 2012 ; Santos 2012 ; Sagredo et al. 2012 ; Di Iorio et al. 2013 ) . Cannabinoids have a benefi cial impact on TMEV infections and may regulate CD200-CD200R interactions (Loria et al. 2008 ; Mecha et al. 2013 ; Mestre et al. 2005 Mestre et al. , 2006 Mestre et al. , 2009 . Cannabinoids may contribute to neurogenesis by antagonizing NO production (Kim et al. 2006b ). In ischemia (Belayev et al. 1995 ) or persistent Bornavirus infections (Solbrig et al. 2013 ; Hooper et al. 2001 ) where NOS-2 is overactive, NO is associated with pathology, cannabinoids are benefi cial. In contrast, in infections where host infl ammation and NO are essential to control CNS disease, cannabinoids promoted pathology (Reiss 2010 ; Herrera et al. 2008 ) . I speculate that cannabinoids may protect the BBB integrity in those settings.

An indirect anti-infl ammatory effect of cannabinoids had been found with activation of the nuclear transcription factor p eroxisome p roliferation a ctivating r eceptor ( PPAR ) family, described below. CB 2 receptor activation may lead to release of endogenous opioids, which inhibit infl ammatory pain (Ibrahim et al. 2006 ) . Somewhat unexpectedly, the antinociceptive and anti-pyretic effects of acetaminophen (Tylenol™) may be due to binding CB 1 receptors.

Δ 9 -Tetrahydrocannabinol treatment decreases host resistance to HSV-2 infection (Cabral et al. 1987 ) , probably by inhibiting host infl ammatory immune responses against the virally infected cells. In several models where infl ammation contributes to pathology, such as TMEV, the synthetic cannabinoid WIN 55,212-2 ameliorates clinical disease (Croxford and Miller 2003 ) ; WIN 55 may also induce PGE 2 production (Mestre et al. 2006 ). However, cannabinoids may contribute to syncytia formation in HIV-E (Noe et al. 1998 ), leading to pathology . In VSV infection of neuronal cells, activating the CB 1 receptor leads to ~15-fold enhanced viral replication via inhibition of Ca 2+ -fl ux and thus impairing the activity of constitutive NOS-1 (Herrera et al. 2008 ) . Therefore, there is no hard and fast rule about the impact of cannabinoid activity on viral infection [reviewed in (Reiss 2010 ) ]. Caution is urged when considering use of these drugs; the effect(s) may be on reticuloendothelial cells or on neurons.

The fi rst part of this section will be devoted to eicosanoids , lipid mediators derived from arachidonic acid, liberated from cell membranes by Phospholipase A 2 . These include prostaglandins (PG), leukotrienes (LT), lipoxins, epoxides, resolvins, marensins, and other bi-products. The second part of the section will include exogenous sources of these metabolites and lipid modifi cation of cellular proteins. Cannabinoids were just discussed. PPAR agonists and Sex hormones will be discussed below; HPAI axis and neuroendocrine regulation are included here.

The sphingolipid Sphingosine-1-phosphate ( S1P ) regulates lymphocyte traffi c from lymph nodes to circulation; it may be bound to the lipid complex HDL in blood (Wilkerson and Argraves 2014 ). Lymphocytes may express two different receptors S1PR1 and S1PR2; S1PR5 is found on endothelial cells (van Doorn et al. 2012 ) . This pathway has been therapeutically targeted with the drug Fingolimod, an S1P agonist also called FTY720, to sequester proinfl ammatory T cells away from sites, such as myelin sheaths in multiple sclerosis (Martin and Sospedra 2014 ; Halmer et al. 2014 ). Females express a higher level of S1PR2 than males (Cruz-Orengo et al. 2014 ) , and this may contribute to sex-bias in some autoimmune diseases and responses to infections. I propose that in proinfl ammatory viral infections of the CNS, where infi ltration of cells from circulation contributes to pathology (example: LCMV , although data were not promising (Carr et al. 2013 ) ), use of the S1P agonist may be indicated.

Prostaglandins (PG) : Cyclooxygenase (COX) 1 and 2 are the enzymes responsible for the pathway from arachidonic acid leading to the formation of distinct PGs and thromboxane (Ueno et al. 2005 ) . PGJ 2 will be discussed below as an agonist for the nuclear transcription factor PPAR. The family of receptors for PGs is among the 7-transmembrane serpentine surface molecules. The end products have many biologic effects ranging from platelet aggregation (TXA 2 ) to infl ammation and fever (PGE 2 ) (Ushikubi et al. 2000 ) , but also a profound consequence is immunoregulation, modulating dendritic cell maturation, differentiation, cytokine secretion, and antigen presentation (Harizi and Gualde 2006 ) . The importance of these molecules in physiological processes and pathology has led to drug discovery efforts (Claria 2003 ) . Nonsteroidal anti-infl ammatory drugs that block the production of PGs have been shown to be anti-infl ammatory in the CNS and somewhat protective for neurodegeneration and cognitive decline in neuroinfl ammatory diseases (Auriel et al. 2014 ) and schitzophrenia (Muller et al. 2013 ).

In the CNS, PGs compromise host responses to VSV, TMEV, JEE, Bornavirus, HSV-1, HIV, enterovirus 71, and EMCV infections (Mestre et al. 2006 ; Chen and Reiss 2002a ; Chen et al. 2000 Chen et al. , 2002 Reynolds and Enquist 2006 ; Steer and Corbett 2003 ; Lima et al. 2006 ; Hooks et al. 2006 ; Rohrenbeck et al. 1999 ; Tung et al. 2010 ; Bertin et al. 2012b ). The mechanism of interference involves suppression of NO production by NOS isoforms (Chen et al. 2002 ) . Therefore NSAIDs and COXIBs are benefi cial not only to prevent fever, aches, and pains, but also to promote recovery from viral infection (Chen and Reiss 2002a ; Steer and Corbett 2003 ) .

: 5-Lipoxygenase (5-LO) is the enzyme responsible for LT formation. In general, there is a dynamic ying-yang relationship between the balance of COX and 5-LO activity, since they both use the same initial substrate, arachidonic acid. There are two groups of LT that contribute to pathophysiology based on the receptors used and whether the LT contain cysteine. The CysLT (LTA 4 , LTC 4 , LTD 4 ) are associated with fl uid production, fi brosis, and airway infl ammation in asthma and other pulmonary diseases, while LTB 4 is a potent chemoattractant of neutrophils (Ogawa and Calhoun 2006 ) . High levels of LT are seen secondary to mast cell infi ltration or Th2-biased host responses patients infected with RSV, HIV, and CMV viruses (Fullmer et al. 2005 ; Flamand et al. 2004 ; Gosselin et al. 2005 ). More importantly, in the CNS, rather than contribute to pathology and BBB disruption, LT play a benefi cial role in recruiting neutrophils and promoting recovery from VSV encephalitis (Chen et al. 2001 ) . LT inhibit early stage HIV infection of microglia (Bertin et al. 2012a ), but contribute to recruitment of CD4+ cells by astrocytes (Bertin et al. 2014 ) . Those individuals who take nonsteroidal anti-infl ammatory drugs will produce more LT, while those with asthma being treated with LOX inhibitors will have more PG; these common medications can have profound consequences on acute or latent viral infections.

Omega-3 fatty acids consumed in diets rich in cold-water fi sh (or by capsules) are also anti-infl ammatory. They attenuate cytokine production and COX activity, downregulate adhesion molecules, and promote recovery from spinal cord injury (De Caterina et al. 2004 ; Morris et al. 2006 ; Serhan 2005b ; King et al. 2006 ; Su et al. 2014 ). Dietary ω-3 fatty acids may prevent or delay Amyotrophic Lateral Sclerosis (Fitzgerald et al. 2014a ) . In infections, the data are mixed with benefi t in HIV, RSV, HBV, infl uenza, and HSV keratitis (Razzini and Baronzio 1993 ; Wu et al. 2012 ; Bryan et al. 2005 ; Tam Vincent et al. 2013 ; Rajasagi et al. 2013 ), but more rapid death in lymphoma associated with the Murine leukemia virus RadLV (Potworowski et al. 1992 ) . Thus, when host infl ammation is essential for controlling viral infection, the immune dampening of ω-3 fatty acids contributes to disease.

Lipoxins (LX) are anti-infl ammatory products of arachidonic acid; 15-epi-LXA 4 is produced in the presence of aspirin. They are produced at temporally and spatially distinct sites from the infl ammatory LT; LX signal through SOCS2 (Machado et al. 2006 ; Serhan 2005a ) . LXA 4 and 15-epi-LXA 4 were associated with attenuation of neural stem cell proliferation and differentiation, in contrast to the activity of LTB 4 , which induced proliferation (Wada et al. 2006 ). The literature is sparse concerning the contribution of LXs in the resolution of infl ammation associated with viral infections (Shirey et al. 2014 ; Russell and Schwarze 2014 ) ; however, it is possible that LX are produced in the CNS during viral infections.

11,12-Epoxyeicosatrienoic acid (EET) and hydroxyleicosatetraenoic acid (HETE) are the products of Cytochrome P450 Epoxygenase, and are also antiinfl ammatory, probably through activation of the PPAR nuclear transcription factor family (discussed below) (Node et al. 1999 ). However, HETEs can also be produced in oxidative damage; they were elevated in plasma of Dengue virus infected people (Seet et al. 2009 ). 15-HETE was anti-apoptotic in EBV-transformed B cells natoni (Belfi ore et al. 2007 ) . 15-and 20-HETE regulate cerebral blood fl ow, enhancing perfusion (Gebremedhin et al. 2000 ) .

Resolvins : Additional anti-infl ammatory lipid molecules are Resolvins and Protectins, which are produced late in infl ammation and promote resolution , including in HSV infection (Bannenberg et al. 2005 ; Russell and Schwarze 2014 ) . The mechanism by which resolvins promote resolution of infl ammation is via induction of miRNA that downregulate proinfl ammatory mRNA (Recchiuti and Serhan 2012 ) .

Statins (HMG CoA inhibitors) were developed and licensed to block cholesterol biosynthesis; however, data indicate that statins diminish infl ammation. Bisphosphonates block bone resorption by acting on osteoblasts. Farnesyl transferase (motif CAAX, found in some proteins with an unpaired Cys) inhibitors were hoped to inhibit cellular Ras family activity and thus be powerful cancer therapeutics. These three classes of drugs block distinct enzymes in the same lipid biosynthetic pathway and therefore contribute to regulation of cell autonomous and systemic innate immunity.

These inhibitors of protein-lipid modifi cation can be anti-infl ammatory, in part, because protein isoprenylation contributes to production of monokines like IL-1 (Mandey et al. 2006 ). TLR4 signaling is impaired by statins (Methe et al. 2005 ) , as is LPS-induced AKT phosphorylation (Patel and Corbett 2004 ) . Cytokine activation of microglia is negatively regulated by RhoA, which prevents NF-k B activation. RhoA negatively regulates COX-2 expression, leading to increased PGs levels when isoprenylation is inhibited (Degraeve et al. 2001 ). These drugs suppress both chemokine production and chemokine receptor expression (Veillard et al. 2006 ) .

However, bisphosphonate treatment results in sustained activation of Rac, Cdc42, and Rho (Dunford et al. 2006 ) , possibly because isoprenylation of phosphatases (PTPases) including the PRL family ( p hosphatase found in r egenerating l iver) regulates the activity of Rac (Fiordalisi et al. 2006 ) . Rho/Rho-kinase activity modifi es actin cytoskeletal proteins and results in dynamic cellular shape changes as well as the activation of NOS-3, resulting in the production of NO and thus, endothelial cell relaxation; inhibition of protein isoprenylation inhibits this cytoskeletal plasticity and changes in blood-fl ow dynamics (Rikitake and Liao 2005 ) . These drugs may diminish infl ammation by inhibiting diapadesis of infl ammatory cells (Walters et al. 2002 ) . Statin treatment is benefi cial therapy in multiple sclerosis, not by inducing Th2 or Treg cells, but by inhibiting proliferation of infl ammatory T cell (Weber et al. 2014b ).

Protein isoprenylation is essential for formation of functional clusters of proteins tethered to cellular membranes (Liao and Laufs 2005 ) . Among the functional complexes which require lipid modifi cation for effective enzymatic activity are the small G TPase a ctivating p roteins (GAPs) including RhoGAP (Ligeti and Settleman 2006 ) . Monocyte anti-bacterial activity associated with NADPH oxidase, activated by Rac guanine nuclear exchange factor is negatively regulated by statins (Mizrahi et al. 2005 ) . Ras must be farnesylated to interact with phosphoinoside-3-kinase (Rubio et al. 1999 ) .

With respect to viral infections, there have been several reports that protein isoprenylation is essential to replication of HBV, HCV, HDV, RSV, infl uenza, and HIV (Acheampong et al. 2007 ; Einav and Glenn 2003 ; Mehrbod et al. 2014 ; Gower and Graham 2001 ; Huang et al. 2006 ; Kapadia and Chisari 2005 ) . VSV replication in neurons is inhibited ~15-fold by one of the drugs (D'Agostino, unpublished). In HIV-E, statin treatment was unsuccessful in inhibiting the release of virus to CSF (Probasco et al. 2008 ) , and there was a slight increase in the risk of developing herpes zoster (Antoniou et al. 2014 ).

Bisphosphonates treatment was benefi cial in RSV infections, but contributed to human metapneumovirus pathogenesis (Kolli et al. 2014 ) . They were benefi cial in HIV infection by blocking the retroviral integrase (Agapkina et al. 2014 ). Neuropathology associated with TMEV infection was controlled by bisphosphonates and by SHP-1, a protein tyrosine phosphatase (Christophi and Massa 2009 ).

Membrane fusion , which is important to initiate many virus infections or to release enveloped virus progeny, is inhibited by isoprenylated SNAREs (Grote et al. 2000 ) . Isoprenylated proteins are not incorporated into lipid rafts (Melkonian et al. 1999 ). An IFN-inducible antiviral protein, h uman G uanylate-b inding p ro-tein-1 (hGBP-1), a GTPase, is isoprenylated, and Golgi-associated, thus its activity is impaired in the presence of pathway inhibitors (Modiano et al. 2005 ) . Dengue virus assembly was inhibited by statins (Martinez-Gutierrez et al. 2011 ). Thus, statins, bisphosphonates, or isoprenyl transferase inhibitors may inhibit viral replication, but may also suppress the host IFN-dependent antiviral pathway(s) and infl ammation. Overall, inhibition of protein isoprenylation is benefi cial to hosts in a wide range of viral infections .

Plasma levels of Vitamin D and its biological activity are regulated by many factors including diet, sun exposure, and polymorphisms that regulate its receptor and plasma binding protein. In addition to regulating cytokine expression, Vitamin D positively regulates human antimicrobial peptides including Defensins (Wang 2014 ) . Low levels of Vitamin D have been associated with infl ammatory diseases including infl ammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, and asthma (Wobke et al. 2014 ) . Low Vitamin D levels are also associated with increased susceptibility to infections including bacterial, parasitic and HCV, HIV, and infl uenza (Havers et al. 2014 ; Kitson et al. 2014 ; Bryson et al. 2014 ; Lang et al. 2013 ) .

In the CNS, low Vitamin D levels are a risk factor for multiple sclerosis (Disanto et al. 2012 ) , and normal levels were observed to be neuroprotective and benefi cial for maintaining cognition (Anastasiou et al. 2014 ) . Experimental sunlight or ultraviolet light exposure inhibited spinal cord infl ammation and reduced demyelination (Wang et al. 2015 ) . In ALS, Vitamin D supplementation may be therapeutic (Gianforcaro and Hamadeh 2014 ) . Serum levels of Epstein-Barr virus were negatively correlated with levels of Vitamin D (Lucas et al. 2011 ); EBV infection is associated with susceptibility to MS in some individuals (Cocuzza et al. 2014 ) . The mechanism of neuroprotection may be impairment of CD4 extravasation across the BBB (Grishkan et al. 2013 ) . Vitamin D levels have not been studied in other neurotropic viral infections, but we may speculate that normal concentrations may be protective.

Many different classes of proteins are critically involved in innate immunity in the CNS. This section will briefl y describe the roles of Defensins, Lactoferrin, Complement cascade components, Cytokines and Chemokines. IFNs were discussed earlier.

Defensins are small, conserved antimicrobial peptides, produced by many cell types including epithelial and leukocytes, which are found in both very primitive species which lack adaptive immunity and mammals. While infl ammatory infi ltrating cells may also contribute, in the CNS parenchyma, defensins are synthesized by astrocytes, the choroid plexus , and the hypothalamus (Evans and Harmon 1995 ; Angeli et al. 1994 ; Williams et al. 2012 Williams et al. , 2014b . Peripherally synthesized defensin molecules can cross the BBB (Schluesener and Meyermann 1995 ) . They have been shown to contribute to elimination of both bacteria and to virus infections by many mechanisms (Wiens et al. 2014 ; Wilson et al. 2013 ) . In viral infections of the CNS , these include HIV, VZV, HSV, Dengue, adenovirus, and JC (Klotman and Chang 2006 ; Crack et al. 2012 ; Rothan et al. 2012 ; Gwyer Findlay et al. 2013 ; Wang 2013 ; Zins et al. 2014 ) . The release of defensins may be regulated by LTB 4 (Flamand et al. 2004 ) .

Lactoferrin is a small secreted, iron-complexed protein that has both antibacterial and antiviral activity. Lactoferrin is found in milk and plasma and secreted by neutrophils (Baynes and Bezwoda 1994 ) . Recent studies suggest that it may contribute to inhibition of innate immune responses during CNS infections with picornaviruses, alphaviruses, papovaviruses, EBV, and HSV (Seganti et al. 2001 ; Waarts et al. 2005 ; McCann et al. 2003 ; Drobni et al. 2004 ; Valimaa et al. 2009 ; Zheng et al. 2012 ) .

Complement cascade components and their receptors are expressed both constitutively and can be induced during immune responses in the CNS. Of course, in the classical cascade, specifi c antibody must fi rst be synthesized and engage its epitopes, inducing conformational changes in IgG which result in exposure of the cryptic C1q binding site and the initiation of the cascade. The alternative and lectin pathways can also induce activation of complement. IgG can cross the BBB, and can, under circumstances of persisting immune responses, be synthesized in the CNS in tertiary lymph nodes (Phares et al. 2013 ) . But that refl ects adaptive and not innate immune responses.

The small anaphylatoxins, C3a, C4a, and C5a, which are proteolytic products of the zymogens, are potently active as activators of vascular permeability and chemoattractants for neutrophils. These molecules are produced in the CNS by astrocytes and microglia (Bruder et al. 2004 ). C5a is a potent recruiter of polymorphonuclear leukocytes (PMNs) . In VSV encephalitis C5a was not required for host responses (Chen and Reiss 2002b ) , the redundance of chemokines and LTB 4 were suffi cient to promote recovery.

Complement receptors include both serpentine 7-transmembrane molecules (which bind C3a, C4a, and C5a) G-protein coupled transmembrane glycoproteins. Endothelial cells and neurons express some complement receptors, including CD46, a measles virus, and Human herpes virus-6 (HHV-6) receptor (Santoro et al. 2003 ; Schneider-Schaulies et al. 2001 ; Shusta et al. 2002 ) . Rabies virus infection of the CNS induces the expression of complement genes (Zhao et al. 2011 ) . Complement activation has also been shown to be critical for the development of the adaptive Ab response for WNV (Mehlhop et al. 2005 ; Dietzschold et al. 1995 ) . In the presence of antibody, exacerbated C3-dependent pathology was observed in MHV-A59, TMEV, and Coxsackie B3 infections (Burrer et al. 2007 ).

The complement lectin pathway contributes to protection from West Nile virus infection (Fuchs et al. 2011 ) . Complement contributes to the neurovirulence of Sindbis, HIV, SIV, and Bornavirus infections (Bruder et al. 2004 ; Speth et al. 2004 ; Griffi n et al. 1997 ; Dietzschold et al. 1995 ; Johnston et al. 2001 ; Phares et al. 2013 ) . In TMEV infection, complement activation contributes to seizures (Libbey et al. 2010 ) . HSV, vaccinia, and the murine gamma herpes virus MHV-68, have developed evasive proteins that prevent complement activity and contribute to their disease pathogenesis (Kapadia et al. 2002 ) .

A vaccinia virus protein has been isolated and has been proposed as a therapeutic when host complement activation is pathogenic in the CNS (Pillay et al. 2005 ) . Recombinant HSV-1 defi cient in the complement-interacting γ134.5 gene product has been proposed as an effective vector for viral oncolysis (Broberg and Hukkanen 2005 ) . Similarly, herbal proteins are also able to block complement and have been suggested as potential neuroprotective therapeutics (Kulkarni et al. 2005 ) . In experimental infection with enterovirus 71 (EV71), a fusion protein of complement receptor 2 (CR2) and the inhibitor Crry prevented complement activation, alleviating local infl ammation , and preventing severe disease associated with the picornavirus (Qiu et al. 2012 ) .

Chemokines : IFNs induce expression of chemokines including IFN-inducible 10KD protein (IP-10; CXCL-10; which also has anti-angiogenic activity), Mig/ Crg-2 (CXCL-9), and I-TAC (CXCL11). These proteins may also have defensin-like activity, nonspecifi cally arming anti-microbial responses (Cole et al. 2001 ). These chemokines recruit neutrophils, natural killer (NK) cells, monocytes, and T cells to the brain (Williams et al. 2014b ) . They have been shown to be important in the host's response to LCMV, MHV, VSV, and TMEV infections (Rubio et al. 2006 ; Asensio et al. 1999 ; Ireland and Reiss 2006 ; Liu et al. 2000 ; Palma and Kim 2001 ) . Fractalkine (C3XCL1) has been associated with recruitment of microglia, brain macrophages, and peripheral cells in HIV dementia (Cotter et al. 2002 ) . Chemokine receptors CCR2 and CXCR3 are essential for recruitment of peripheral cells during SFV and WNV encephalitis (Michlmayr et al. 2014 ).

Many molecules have chemoattractant activity, but are not in the peptide families of chemokines. These include the cytokine IL-12, produced by antigen presenting cells, that can recruit NK cells (Michel et al. 2012 ) , the bacterial tri-peptide f-MetLeuPhe, and the leukotriene LTB 4 for neutrophil recruitment (Lefebvre et al. 2011 ) .

Cytokines are comprised of dozens of different protein mediators, which are generally secreted by one cell and act on the secreting cell (autocrine), locally (paracrine), or systemically (endocrine) to either activate and differentiate another cell type, or regulate the activity of another cell. Generally, the receptors are heterodimers of surface glycoproteins, signaling through tyrosine kinase cascades. Although many investigators have tested the effects of individual molecules in experimental systems, in real life, cytokines are secreted as a part of a coordinated program with many different molecules (including receptor antagonists) released at the same time; it is the composite of these mediators' signal transduction pathways that lead to the outcome. The differentiation state of the downstream cell, the quantity, and duration of exposure determine the response. Cytokines can downregulate their receptors by internalization, leading to desensitization, or induce enhanced expression of their own (and other) receptor and second messengers, which can positively regulate subsequent responses.

In the brain these molecules can be produced by both parenchymal cells and infi ltrating infl ammatory cells . Two excellent reviews of cytokines and the CNS are a book edited by Ransohoff and Benviste and an article by Campbell (Ransohoff and Benveniste 2005 ; Campbell 2005 ) . It is the balance between proinfl ammatory cytokines such as TNF-α, IL-17, or IL-23 and the anti-infl ammatory molecules such as IL-4, TGF-β, or IL-10 that ultimately determine the outcome.

Systemically produced cytokines can lead to CNS consequences ranging from the fever response to IL-1 (inducing the production of PGE 2 ) or TNF-α secretion, resulting in transient disruption of the BBB. Excessive peripheral release of cytokines has been associated with "sickness behavior" (Dantzer 2005 ; Watkins and Maier 2000 ) .

In infections, proinfl ammatory cytokines can lead to benefi cial outcomes, such as IL-12, TNF-α, or IFN-γ induction of NO which leads to elimination of VSV infections (Komatsu et al. 1996 (Komatsu et al. , 1997 (Komatsu et al. , 1999a Ireland and Reiss 2004 ; Ireland et al. 1999 Ireland et al. , 2005 ; however, IL-12/IL-23 and IL-18 are not necessarily critical even if synthesized or administered (Hodges et al. 2001 ; Ireland et al. 2005 ) . These are important in Sindbis, TMEV, and MHV infections (So et al. 2006 ; Binder and Griffi n 2003 ; Lane et al. 1996 ; Olson and Miller 2009 ; Rempel et al. 2004 ). Excessive expression of proinfl ammatory cytokines, in other circumstances, may contribute to pathology (neurovirulence or neurodegeneration) in Bornavirus, JEV, HTLV-1, HIV/SIV, MHV, TMEV, enterovirus 71, LCMV, canine distemper, rabies, and VEE. The proinfl ammatory cytokine IL-27 induced IL-10 production in MHV-A59 infection, leading to increased demyelination and reduced control of viral replication (de Aquino et al. 2014 ) . Ironically, the anti-infl ammatory cytokine IL-4 may be associated with resistance to human WNV infection in a GWAS study (Qian et al. 2014 ) . Cytokines are essential mediators in viral infections of the CNS. Some cytokines are neuropoietic, promoting recovery (Bauer et al. 2007 ). The timing, quantity, and balance of these bioactive molecules determine the outcome: recovery or pathology.

Many transcription factor families regulate responses, and the roles of IFN-inducible STATs have been discussed above. In this section, three classes of transcriptional factors will be described: Hypoxia-inducible factor, Peroxisome proliferation activating receptor, and High mobility group-1 protein. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor whose expression is triggered by transient hypoxia (or ischemia/ stroke); it induces the expression of a number of genes including defensins, the adenosine A 2 B receptor, Vascular Endothelial Growth Factor (VEGF), COX-2, NOS-2, and NOS-3 (Kong et al. 2006 ; Hellwig-Burgel et al. 2005 ; Peyssonaux and Johnson 2004 ) . VEGF regulates not only BBB permeability, but also angiogenesis. HIF-1α expression can be induced by IL-1, TNF-α, and possibly TLR agonists (Hellwig-Burgel et al. 2005 ; Argaw et al. 2006 ) . It is expressed during infl ammatory and demyelinating diseases (Aboul-Enein et al. 2003 ) . In studies with viral vectors for oncolysis in the CNS, HIF-1α expression was enhanced (Shen et al. 2006 ; Post et al. 2004 ). Thus, HIF-1α expression , whether elicited by transient vascular compromise or cytokine expression, enhances the innate antiviral (and anti-bacterial) gene expression and may lead to increased BBB perfusion of the local area.

Peroxisome Proliferating Activating Receptors , nuclear hormone transcription factors, have three isoforms α, β, and γ, each with distinct activity and expression. PPAR-γ, the canonical nuclear hormone receptor involved in muscle glucose uptake and lipid homeostasis and cell differentiation, is translated as two splice variants, γ1 and γ2. PPAR-γ2, 30 amino acids longer than γ1, is expressed in high levels of adipose tissue. PPAR-γ ligands are polyunsaturated fatty acids, eicosanoids, FA oxidation products (13-HODE and 15-HETE), J-series prostaglandins (15-deoxy-D12,14-prostaglandin J 2 ), some nonsteroidal anti-infl ammatory drugs (NSAIDS), and insulin sensitizing thiazolidinediones (TZDs). PPAR-γ functions as an obligate heterodimer with Retinoic X receptor (RXR) to activate transcription by binding to 5′ promoters of target genes (Grygiel-Gorniak 2014 ; Fidaleo et al. 2014 ) .

PPAR-γ agonists modulate infl ammatory responses in the CNS, resulting in the reduction of iNOS in cerebellar granule cells. PPAR-γ signaling has anti-infl ammatory function in EAE, PPAR-γ agonists alleviate symptoms with antagonists performing the opposite, indicating regulation of auto-reactive Th1 and Th17 cells (Kanakasabai et al. 2010 ) . PPAR-γ also can regulate pathologic immune responses within the CNS in MS (Shukla et al. 2010 ). Alzheimer's disease is a severe neurodegenerative disease characterized by the accumulation of amyloid plaques accompanied with activated microglia. TZD treatment in in vitro experiments with microglia and monocytes attenuated the secretion of proinfl ammatory cytokines. Medium from TZD-treated microglia was neuroprotective (Drew et al. 2006 ) .

Infection by Adenovirus 36 induces PPAR expression, and increases insulin sensitivity (Pasarica et al. 2006 ) . In vitro treatment of cells with PPAR agonists inhibited replication of RSV, HHV8, HCV, HIV, and VSV (Rakic et al. 2006 ; Bryan et al. 2005 ; Arnold and Konig 2006 ; Herrera et al. 2008 ) , although the mechanism(s) by which this inhibition occurred have not been elucidated. However, HBV X-associated protein 2 complexes with PPAR and inactivates it (Sumanasekera et al. 2003 ) , an evasive pathway. Thus treatment with PPAR agonists, such as TZDs, may be beneficial for treatment of viral encephalitis both as potential antiviral compounds, and as anti-infl ammatory drugs in infections where pathology is associated with infl ammation , such as Bornaviral disease and HIV infection (Kim et al. 2012 ) .

High Mobility Group protein B1 (HMGB1) is unique among transcription factors as it is found not only in the nucleus, but also in the cytoplasm associated with α-Synuclein fi laments (Lindersson et al. 2004 ) and is actively released as an alarmin. Its expression may be upregulated by IFN (Seeler et al. 2001 ) . HMGB1 may engage AMIGO receptors of neurons where it regulates neurite outgrowth, TLR 2 and TLR 4, or the Receptor for Advanced Glycation Endproducts (RAGE) which results in a proinfl ammatory response by microglia, macrophages, and dendritic cell maturation (O'Connor et al. 2003 ). HMGB1 release has been shown to be neurotoxic in ischemia, Alzheimer's disease (Kim et al. 2006a ) and in Bornavirus disease, HTLV-1, HIV-1, and WNV infections (Troseid et al. 2013 ; Kimura and Mori 2014 ; Zhao et al. 2006 ; Chu and Ng 2003 ) . HMGB1 is a Janus molecule with both regulatory transcriptional activity and signaling of tissue damage; it may be important in eliciting innate immunity during viral encephalitis.

Within the CNS, there are anatomically distinct regions that have some constitutive vascular permeability (Circumventricular organ, choroid plexus, for example), but most areas are highly restricted in access to circulating cells and proteins. Astrocytes regulate the perfusion of the parenchyma by controlling vasodilation of the cerebrovascular capillaries through the activity of NOS-3 (Sporbert et al. 1999 ; Komatsu et al. 1999b ). The BBB is associated with the immune privilege of the brain and separates the CNS from peripheral circulation and immune surveillance that is characteristic of the periphery. Entry of cells requires adhesion to the brain microvascular endothelium, release of MMPs to degrade tight junctions and the extracellular matrix, as well as migration along a gradient of chemoattracting molecules (Bechmann et al. 2007 ; Arima et al. 2013 ) . The chemoattracting molecules for circulating cells range from LTB 4 to complement products, chemokines, cytokines, FLT3L, and even ATP (all discussed in the relevant sections, above).

The BBB breakdown associated with infection results from excessive normal physiological process regulating blood fl ow within the CNS (Proescholdt et al. 1999 ; Abbott et al. 2006 ) . Activation leads to NOS-3-expressing astrocytes to release NO, which induces guanadyl cyclase to produce cGMP, leading to endothelial and smooth muscle cell relaxation. Other mediators such as the small complement cascade mediators C3a, C4a and C5a, VEGF and PGE 2 can also lead to the relaxation and increased permeability of the BBB .

A hallmark of many viral infections including VSV, Rabies, Flaviviruses, HIV, TMEV, and WNV (Daniels et al. 2014 ; Wang et al. 2013 ; Neal 2014 ; Johnson et al. 2014 ; Williams et al. 2014a ; Chen et al. 2002 ) is the breakdown of the BBB. However the global breakdown of the BBB seen in fatal LCMV (Kang and McGavern 2010 ) and in fatal VSV infections is extreme, and unusual. In most cases, the overall integrity of the BBB is maintained, but in discrete regions, there is increased perfusion leading to entry of normally excluded proteins from circulation.

Cells under stress from viral infection, TNF-family cytokines, CTL recognition, as well as many other stimulate can undergo programmed cell death (apoptosis) (Danial and Korsmeyer 2004 ). I will not review the cellular pathways which lead to genome fragmentation and membrane inversion, but will focus, instead, on associations between viral infection and apoptosis. Cells which commit suicide in this manner may spare the host from continued viral replication, a benefi t, especially since most cells can be replaced by stem cells in that organ; however, if the infected cell undergoing apoptosis were a neuron , signifi cant consequences might ensue (Perkins 2005 ) .

Neurotropic viruses which elicit apoptosis include alphaviruses (Griffi n 2005 ), Flaviviruses (Clarke et al. 2014 ), Picornaviruses (Ruller et al. 2012 ) , VSV (Gaddy and Lyles 2007 ) , Rabies (Fu and Jackson 2005 ) , coronaviruses (Desforges et al. 2014 ) , LCMV , reovirus (Dionne et al. 2013 ) , JC (Merabova et al. 2012 ) , HIV-1 (Geffi n and McCarthy 2013 ), and HTLV-1 (Marriott and Semmes 2005 ) . In fact, apoptosis is such an important cellular defensive response to viral infections that poxviruses have developed an evasive pathway, using ser ine p rotease in hibitors (serpins) (Taylor and Barry 2006 ) . But, scientists are clever and have selected apoptosis as a tool for viral oncolysis.

At other times, viral infections or cellular stress from starvation can lead to recycling of large volumes of cytoplasmic contents by generation of vesicles which fuse with lysosomes ( autophagy , self-eating) (Deretic 2005 ) . This pathway can become dysregulated, resulting in infl ammation and neurodegenerative diseases (Deretic et al. 2013 ; Noch and Khalili 2013 ; He and Klionsky 2006 ) . Some picornaviruses use this cellular response to develop additional membranes on which to replicate (Korom et al. 2013 ) autophagy-associated pathology has been reported. Thus, in general, autophagy is an innate host cellular response to suppress viral infection, however, some viruses, to their benefi t, can manipulate it.

Normally there are very few lymphocytes, neutrophils, and NK cells in brain parenchyma. Infi ltration of infl ammatory cells ranging from PMNs to NK cells to macrophages and fi nally lymphocytes takes place in response to a series of signals from both chemoattractant molecules and orchestrated binding to microvascular endothelial cell surface molecules (Williams et al. 2001 ; Luster et al. 2005 ) . For cells to cross the endothelial vessel wall, they must diapedese and then digest the basement membrane with MMPs. This review will not discuss the infi ltration of antigenspecifi c T cells or B cells, as it is limited to innate immune responses.

Neutrophils are the fi rst cell to infi ltrate sites of viral infection. Chemoattractants for neutrophils include Adenosine, ATP, f-MetLeuPhe, C5a, LTB 4 , and chemokines (Gabriel et al. 2013 ). As described above, they produce defensins, cytokines, media-tors from aracodonic acid, and other bioactive compounds. In VSV encephalitis, LTB 4 and chemokines, but not C5a, are essential (Ireland and Reiss 2006 ; Chen and Reiss 2002b ; Chen et al. 2001 ) . PMN infi ltration is also characteristic of Murray Valley encephalitis, MHV, HSV-1, TMEV, Western equine encephalitis, and adenovirus infections (Libbey et al. 2011 ; Weiss et al. 2007 ; Matthews et al. 2000 ; Reed et al. 2005 ; Wakimoto et al. 2003 ; Welsh et al. 2004 ; Weinberg et al. 2007 ; Zhou et al. 2003 ; Campbell et al. 2001 ; Bell et al. 1996 ) .

NK cells are generally the second cell type to diapedese in response to viral infections of the CNS in response to both chemokines and IL-12. NK cells nonspecifi cally recognize patterns of receptor expression on cells and are sensitive to low levels of MHC molecules, and, when activated, release IFN-γ, perforin and granzymes, like CD8 + CTL. NK cells have been associated with the host response to JEV, WNV, Sindbis, MHV, Bornavirus, EBV, HSV-1, VSV, SIV, CMV, TMEV, and enterovirus 71 (Hatalski et al. 1998 ; Christian et al. 1996 ; Wensman et al. 2011 ; Fernandes et al. 2011 ; Wang et al. 2013 ; Mott et al. 2011 ; Brehin et al. 2008 ; Larena et al. 2013 ; Ogura et al. 2013 ) . NK cells contribute not only lytic activity against virally infected cells, but also are a signifi cant source of IFN-γ secretion, both of which may regulate viral replication .

Pioneering work by the late Helen Cserr and her colleagues including Paul Knopf explored lymphatic drainage of soluble antigens and their ability to evoke an acquired immune response (Knopf et al. 1995 ) . This drainage is polarized from rostral to caudal, and is modest and does not include the hallmarks of peripheral tissue dendritic cells bearing antigens to the draining lymph nodes.

Antigen processing and presentation is at the interface between the innate and adaptive immune responses to pathogens. There is little constitutive expression of Class II MHC molecules in the undisturbed CNS; however, both astrocytes and microglia readily express these molecules in response to infl ammatory cytokines, especially IFN-γ (Gresser et al. 2000 ) . Infection indirectly induces the expression of MHC II and enhances the expression of MHC I by parenchymal cells (Berman et al. 1998 ; Abraham and Manjunath 2006 ; Aguirre and Miller 2002 ; Alldinger et al. 1996 ; Caplazi and Ehrensperger 1998 ) .

Perivascular macrophages have been shown to be an important player in antigen presentation for the brain in infections and autoimmune disease (Williams and Hickey 2002 ) . Macrophages and microglia may produce proinfl ammatory (M1) or antiinfl ammatory (M2) cytokines and bioactive mediators; M2 microglia antagonize neuroinfl ammation (Cherry et al. 2014 ) . Mi cells contain multimolecular complexes called infl ammasomes, intracellular sensors for pathogens and danger signals; these infl ammasomes generate substantial quantities of proinfl ammatory IL-1 and IL-18 (Walsh et al. 2014 ) . M1 microglia are characteristic of VSV, neurotropic infl uenza virus, and TMEV infections (Jurgens et al. 2012 ; Son et al. 2009 ; Steel et al. 2014 ) .

Mast cells are often overlooked except in studies of Type 1 hypesensitivities. Mast cells can participate with glia in neuroinfl ammation (Skaper et al. 2014 ) . IL-33, produced by glia, would promote mast cells; in TMEV infections, IL-33 was produced (Hudson et al. 2008 ) . In HIV-E with immune reconstitution syndrome after antiretroviral therapy, mast cells contribute to CNS pathology (Rushing et al. 2008 ) .

Dendritic cells are the principal antigen presenting cells in the periphery and are a complex group of cells whose phenotypes rival T cell subsets (Guilliams et al. 2014 ; Cohn and Delamarre 2014 ) . They are extremely diffi cult to detect in undisturbed brain tissue. During immune responses in the CNS, it is possible to fi nd cells expressing dendritic cell markers (Matyszak and Perry 1997 ; Ambrosini et al. 2005 ) . In addition to any chemokines, Flt3L has been shown to recruit dendritic cells to the CNS (Curtin et al. 2006 ) . Parenchymal dendritic cells have numerous phenotypes (D'Agostino et al. 2012a ) , and VSV infection induces CD103 + CD11b + cells (D'Agostino et al. 2012b ). Dendritic cell responses are age dependent and may contribute to the susceptibility of immature hosts to some forms of viral encephalitis (Taylor et al. 2014 ). However, the microenvironment during which dendritic cells are exposed to virus can determine whether pro-infl ammatory or Treg responses are found (Durrant et al. 2013 ; Martinez et al. 2014 ).

The hypothalamic-pituitary-adrenal-immune (HPAI) axis controls not only fi ght-orfl ight in response to stressors, but also critical control of immune responses to infections. There are short-term and chronic stress manifestations of this (Eskandari and Sternberg 2002 ; Shanks et al. 1998 ) , with long-term compromise of immune responses to viral infections (Silverman et al. 2005 ) . This may be manifest as alterations in the humoral response to viral infection (Ijaz et al. 1990 ). Acute stress may also alter the integrity of the BBB (Esposito et al. 2001 ) , thus potentially permitting entry to otherwise excluded viruses.

Chemical sympathectomy , achieved by infusion of 6-hydroxydopamine, has profound effects on the peripheral immune response, as there is sympathetic innervation of the spleen and lymph nodes (Callahan et al. 1998 ). Hosts are more susceptible to bacterial, VZV reactivation, and HSV-1 infections (Cao et al. 2002 ; Massad et al. 2004 ; Leo et al. 1998 ; Templeton et al. 2008 ), but when hosts are already immune suppressed, whether by malnutrition or by lentivirus infections, they are not further compromised (Kelley et al. 2002 ; Gonzalez-Ariki and Husband 1999 ) . We tested whether chemical sympathectomy altered the ability of peripheral plasmacytoid dendritic cells to produce IFN-β in response to VSV infection of the CNS, and found no contribution of innervation of secondary lymphoid organs in this response (Trottier et al. 2007 ). However, production of proinfl ammatory cytokines and increased pathology were observed in infl uenza virus infection to be associated with the sympathetic response (Grebe et al. 2010 ).

Cholinergic pathways have been shown to be anti-infl ammatory in bacterial model systems and ischemia-reperfusion injury (Tracey 2007 ) , inhibiting cytokine production and tissue injury in models such as colitis (Sun et al. 2013 ) . In a transgenic model, HIV-1 was associated with learning defi cits; activation of the cholinergic pathway with nicotine did not ameliorate the loss vigorito (Vigorito et al. 2013 ) . But, there are no published reports in the literature on the impact of this regulatory neurotransmitter pathway on neurotropic viral infections.

Leptin was originally identifi ed as the gene product defi cient in obese mice and was found to regulate energy balance, but like so many other effector molecules , has many other activities. Proinfl ammatory cytokines, induced during infections, can upregulate production of leptin , and lead to anorexia (Langhans 2000 ) . Central leptin and insulin resistance has been associated with Adenovirus (SMAM-1 and Ad36) infection, leading to obesity (Wierucka-Rybak and Bojanowska 2014 ). Recent evidence suggests that this adipocyte-produced protein is also immunoregulatory and is, in fact, a proinfl ammatory cytokine (Lord 2006 ) . Leptin is pathogenic in EAE (Matarese et al. 2002 ) by virtue of its action on dendritic cells, resulting in the induction of Th1 responses (Mattioli et al. 2005 ) and its inhibition of thymic apoptosis (Mansour et al. 2006 ) . In experimentally induced obese mice, more severe infl uenza pathology was associated with leptin (Zhang et al. 2013a ). Wellnourished infants, with elevated leptin levels, were more susceptible to Dengue hemorrhagic fever, than were thinner children (Libraty et al. 2014 ) . High leptin levels were observed in HCV-infected people with chronic fatigue symptoms (El-Gindy et al. 2012 ) . In contrast, low levels of leptin are observed in HIV infections, and exaggerated in those patients with lipodystrophy veloso (Veloso et al. 2012 ). Therefore, leptin may be a potential target for therapeutic intervention in persistent infl ammatory infections of the CNS such as HIV-E and Bornaviral disease.

Sex hormones regulate more pathways than just those in secondary sexual organs.

Estrogen is neuroprotective in infection, Alzheimer's disease, traumatic injury, and ischemia (Barreto et al. 2014 ; Cue et al. 2015 ) . Estrogen has profound immunomodulating effects ranging from induction of NOS-3, and thus increased vascular perfusion (Hayashi et al. 1997 ) . Selective estrogen receptor modulators enhance neurogenesis and spine density (Khan et al. 2015 ) . Movement disorders including Parkinson's disease are more frequent in males (Lubomski et al. 2014 ) . Estrogen positively regulates expression of IFN-γ (Fox et al. 1991 ) ; this is clearly linked with the increased frequency of females who have Th1-associated autoimmune diseases such as EAE/MS (Whitacre et al. 1999 ) .

Additionally, sex hormones regulate PPARs, and can infl uence the severity of EAE (Dunn et al. 2007 ) . Females may be more resistant to some viral infections due to enhanced Th1 responses, including VSV, TMEV, and HSV-1 (Markle and Fish 2014 ; Forger et al. 1991 ; Fuller et al. 2005 ; Peter and Sevall 2001 ) .

Androgens may be immunosuppressive by inhibiting Th1 differentiation (Kissick et al. 2014 ) . This may contribute to diminished effi cacy of vaccination and the production of anti-infl uenza antibody by males (Furman et al. 2014 ) . Hepatitis B and HCV disease is more severe in males, and correlated with testosterone levels (Tian et al. 2012 ; White et al. 2012 ) .

There is an effect of host sex in viral infections of the CNS. Female mice are more resistant than males to lethal VSV infections (Barna et al. 1996 ) , and show improved clearance of MHV and Semliki Forest virus infection from oligodendrocytes (Fazakerley et al. 2006 ; Parra et al. 1999 ) . However, female mice undergo more severe demyelination in TMEV infections (Fuller et al. 2005 ) . HIV-E and HIV-dementia incidence may be lower in females due to estrogen effects on immune responses (Wilson et al. 2006 ) . Thus, where infl ammation is benefi cial to clearing virus and resolving infection, females are at an advantage. In contrast, where infl ammation contributes to viral disease pathology in the CNS , females are disproportionately affected.

Innate immunity in the CNS is complex and includes protein effectors (IFNs, cytokines, chemokines, defensins, complement, lactoferrin, and other molecules), lipid mediators (PGs, LTs, Cannabinoids, etc.), small diffusible molecules (NO, ONOO − ), and both parenchymal and infl ammatory cells. These responses are highly regulated and are triggered, in part, by receptors that bind common pathogen-associated or damage-associated molecules. Combined, these responses provide a critical barrier, controlling viral replication until adaptive immune responses are marshalled. Infl ammation is essential, but must be carefully controlled to prevent tissue damage and pathology. Virtually every pathway has regulation (e.g., kinases and phosphatases) that ultimately determines the magnitude and then the resolution of responses . We are still learning about the essential pathways and their controls, about how drugs may alter the dynamic equilibrium, and in which situations responses need to be ramped up or downregulated. Nonetheless, innate immune responses are critically essential in the central nervous system, to buy the host time for the adaptive immune response to mature and provide antigen-specifi c effector T cells and antibody to the viral infection. I predict we will make many future advances that will benefi t the health of the populations who are infected with neurotropic viruses.

Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V (2013) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503 (7477) 

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Emerging roles for immunomodulatory functions of free ISG15

The effects of restraint stress on the neuropathogenesis of Theiler's virus infection: I. Acute disease

Kynurenines in CNS disease: regulation by infl ammatory cytokines

Sympathetic nervous system plays a major role in acute cold/restraint stress inhibition of host resistance to Listeria monocytogenes

Spontaneous Borna disease in sheep and horses: immunophenotyping of infl ammatory cells and detection of MHC-I and MHC-II antigen expression in Borna encephalitis lesions

Sphingosine kinase 1 in viral infections

Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression

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The 2-5A system in viral infection and apoptosis

Homeostatic interferon expression in neurons is suffi cient for early control of viral infection

Decreased cytomegalovirus expression following proinfl ammatory cytokine treatment of primary human astrocytes

Mechanisms for enveloped virus budding: can some viruses do without an ESCRT?

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NSAID treatment suppresses VSV propagation in mouse CNS

Leukotrienes play protective roles early during experimental VSV encephalitis

Selective inhibition of COX-2 is benefi cial to mice infected intranasally with VSV

Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation

Herpes simplex virus 1 infection activates the endoplasmic reticulum resident kinase PERK and mediates eIF-2alpha dephosphorylation by the gamma(1)34.5 protein

Neuroinfl ammation and M2 microglia: the good, the bad, and the infl amed

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

PKR is not required for interferon-gamma inhibition of VSV replication in neurons

Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis

The endocannabinoid system: a putative role in neurodegenerative diseases

The broad-spectrum antiviral functions of IFIT and IFITM proteins

Signaling pathways in virus-induced CNS infl ammation

Expression of C1q, a subcomponent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis

Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity

Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection

Daxx upregulation within the cytoplasm of reovirus-infected cells is mediated by interferon and contributes to apoptosis

Multiple sclerosis: risk factors and their interactions

Resveratrol counteracts lipopolysaccharide-mediated microglial infl ammation by modulating a SOCS-1 dependent signaling pathway

Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS infl ammatory disorders

Lactoferrin inhibits human papillomavirus binding and uptake in vitro

Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants

Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases

Peroxisome proliferator-activated receptor (PPAR){alpha} expression in T cells mediates gender differences in development of T cell-mediated autoimmunity

IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis

Prenylation inhibitors: a novel class of antiviral agents

Distinct host-dependent pathogenic mechanisms leading to a similar clinical anemia after infection with lymphocytic choriomeningitis virus

Serum leptin level and its association with fatigue in patients with chronic hepatitis C virus infection

Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine

The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection

Neural-immune interactions in health and disease

Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells

A review of antimicrobial peptides: defensins and related cationic peptides

Innate immune mechanisms in Japanese encephalitis virus infection: effect on transcription of pattern recognition receptors in mouse neuronal cells and brain tissue

USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase

VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway

Virus tropism, distribution, persistence and pathology in the corpus callosum of the Semliki Forest virus-infected mouse brain: a novel system to study virus-oligodendrocyte interactions

Interferon-induced Ifi t proteins: their role in viral pathogenesis

Interferon-induced Ifi t2/ISG54 protects mice from lethal VSV neuropathogenesis

The interferon-induced protein, Ifi t2, protects mice from infection of the peripheral nervous system by vesicular stomatitis virus

In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus

Neuroprotective properties of peroxisome proliferator-activated receptor alpha (PPARalpha) and its lipid ligands

PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility

Dietary ω-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis

An evolving arsenal: viral RNA detection by RIG-I-like receptors

Release of anti-HIV mediators after administration of leukotriene B4 to humans

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules

Murine infection by vesicular stomatitis virus: initial characterization of the H-2d system

Estrogen regulates the IFN-gamma promoter

Neuronal dysfunction and death in rabies virus infection

The lectin pathway of complement activation contributes to protection from West Nile virus infection

Gender bias in Theiler's virus-induced demyelinating disease correlates with the level of antiviral immune responses

Role of cysteinyl leukotrienes in airway infl ammation and responsiveness following RSV infection in BALB/c mice

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to infl uenza vaccination

Viral CNS infections: role of glial pattern recognition receptors in neuroinfl ammation

Neutrophils: neglected players in viral diseases

Oncolytic vesicular stomatitis virus induces apoptosis via signaling through PKR, Fas, and Daxx

Assembly and localization of Toll-like receptor signalling complexes

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Innate immune responses to HIV infection in the central nervous system

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An experimental model system for HIV-1-induced brain injury

Vitamin D as a potential therapy in amyotrophic lateral sclerosis

Delta(9)-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity

The alternate triad motif of the poly(ADP-ribose) polymerase-like domain of the human zinc fi nger antiviral protein is essential for its antiviral activity

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Junin virus-induced astrocytosis is impaired by iNOS inhibition

Sympathectomy abrogates immunodefi ciency associated with protein-energy malnutrition

Regulation of immune tolerance by antiinfl ammatory neuropeptides

Reovirus infection of the CNS enhances iNOS expression in areas of virus-induced injury

PKR-dependent and -independent mechanisms are involved in translational shutoff during Sindbis virus infection

Leukotriene B4 protects latently infected mice against murine cytomegalovirus reactivation following allogeneic transplantation

Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates

Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro

Cutting edge: sympathetic nervous system increases proinfl ammatory cytokines and exacerbates infl uenza A virus pathogenesis

Innate immunity to dengue virus infection and subversion of antiviral responses

Tumor necrosis factor alpha and interleukin-1 alpha inhibit through different pathways interferon-gamma-induced antigen presentation, processing and MHC class II surface expression on astrocytes, but not on microglia

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The role of antibody in recovery from alphavirus encephalitis

) 1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization

Geranylgeranylated SNAREs are dominant inhibitors of membrane fusion

Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review

Type III interferon attenuates a vesicular stomatitis virus-based vaccine vector

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Cationic host defence peptides: potential as antiviral therapeutics

Sphingolipids: important players in multiple sclerosis

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Evolution of the immune response in the central nervous system following infection with Borna disease virus

25-Hydroxyvitamin D insuffi ciency and defi ciency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings

Effect of estrogen on isoforms of nitric oxide synthase: possible mechanism of anti-atherosclerotic effect of estrogen

Autophagy and neurodegeneration

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Human cytomegalovirus induced cyclooxygenase-2 in human retinal pigment epithelial cells augments viral replication through a prostaglandin pathway

The central nervous system infl ammatory response to neurotropic virus infection is peroxynitrite dependent

5′-Triphosphate RNA is the ligand for RIG-I

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A viral RNA structural element alters host recognition of nonself RNA

CB2 cannabinoid receptor mediation of antinociception

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Gene expression contributing to recruitment of circulating cells in response to vesicular stomatitis virus infection of the CNS

Delayed administration of interleukin-12 is effi cacious in promoting recovery from lethal viral encephalitis

Interleukin (IL)-12 receptor beta1 or IL-12 receptor beta 2 defi ciency in mice indicates that IL-12 and IL-23 are not essential for host recovery from viral encephalitis

Virus interference. I. The interferon

Regulation of type I interferon responses

Subversion of cellular autophagosomal machinery by RNA viruses

IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication

Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta

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Theiler's murine encephalomyelitis virus as an experimental model system to study the mechanism of blood-brain barrier disruption

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Infl uenza infection induces neuroinfl ammation, alters hippocampal neuron morphology, and impairs cognition in adult mice

HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation

Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis

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HMGB1 in health and disease

Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids

Critical role of complement and viral evasion of complement in acute, persistent, and latent gamma-herpesvirus infection

PKR mediated regulation of infl ammation and IL-10 during viral encephalomyelitis

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

Toll-like receptors and their crosstalk with other innate receptors in infection and immunity

Chemical sympathectomy has no effect on the severity of murine AIDS: murine AIDS alone depletes norepinephrine levels in infected spleen

Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia

HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinfl ammation in the postischemic brain

Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity

) (4)-prostaglandin J(2) inhibits human immunodefi ciency virus-1 tat-induced monocyte chemoattractant protein-1/CCL2 production by blocking the extracellular signal-regulated kinase-1/2 signaling pathway independently of peroxisome proliferator-activated receptorgamma and heme oxygenase-1 in rat hippocampal slices

Abundant expression of HMGB1 in human T-cell lymphotropic virus type I-infected T-cell lines and high plasma levels of HMGB1 in patients with adult T-cell leukemia

Ifi t1 inhibits Japanese encephalitis virus replication through binding to 5′ capped 2′-O unmethylated RNA

Omega-3 fatty acids improve recovery, whereas omega-6 fatty acids worsen outcome, after spinal cord injury in the adult rat

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis

A giant GTPase, very large inducible GTPase-1, is inducible by IFNs

Defensins in innate antiviral immunity

Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fl uid from the brain

MxA GTPase: oligomerization and GTP-dependent interaction with viral RNP target structures

Effects of adenoviral-mediated gene transfer of interleukin-10, interleukin-4, and transforming growth factor-beta on the survival of axotomized retinal ganglion cells

Alveolar macrophages contribute to the pathogenesis of hMPV infection while protecting against RSV infection

Interferon-gamma induced type I nitric oxide synthase activity inhibits viral replication in neurons

Interleukin-12 promotes recovery from viral encephalitis

Neuronal expression of NOS-1 is required for host recovery from viral encephalitis

Regulation of the BBB during viral encephalitis: roles of IL-12 and NOS

HIF-dependent induction of adenosine A2B receptor in hypoxia

A proautophagic antiviral role for the cellular prion protein identifi ed by infection with a herpes simplex virus 1 ICP34.5 mutant

Accelerated development of neurochemical and behavioral defi cits in LP-BM5 infected mice with targeted deletions of the IFN-gamma gene

Inhibition of polyprotein processing and RNA replication of human rhinovirus by pyrrolidine dithiocarbamate involves metal ions

Herpes simplex virus-1 induces expression of a novel MxA isoform that enhances viral replication

Herbal complement inhibitors in the treatment of neuroinfl ammation: future strategy for neuroprotection

Japanese encephalitis virus infection modulates the expression of suppressors of cytokine signaling (SOCS) in macrophages: implications for the hosts' innate immune response

Age-dependent resistance to lethal alphavirus encephalitis in mice: analysis of gene expression in the central nervous system and identifi cation of a novel interferon-inducible protective gene, mouse ISG12

PML nuclear bodies

Expression of infl ammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIVinduced central nervous system disease

Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and infl ammation

How important is vitamin D in preventing infections?

Anorexia of infection: current prospects

Cytolytic effector pathways and IFN-gamma help protect against Japanese encephalitis

A2 adenosine receptors: their presence and neuromodulatory role in the central nervous system

Extra domain A of fi bronectin primes leukotriene biosynthesis and stimulates neutrophil migration through activation of Toll-like receptor 4

Antiviral properties of ISG15

Peripheral sympathetic denervation alters both the primary and memory cellular immune responses to herpes simplex virus infection

Toll-like receptors in antiviral innate immunity

HIV and CXCR4 in a kiss of autophagic death

MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha

VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice

MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-lambda1

Pleiotropic effects of statins

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Interleukin-6, produced by resident cells of the central nervous system and infi ltrating cells, contributes to the development of seizures following viral infection

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Regulation of RhoGAP specifi city by phospholipids and prenylation

The intrinsic antiviral defense to incoming HSV-1 genomes includes specifi c DNA repair proteins and is counteracted by the viral protein ICP0

Interaction of macrophages with apoptotic cells enhances HIV type 1 replication through PGE2, PAF, and vitronectin receptor

The role of IL-10 in mouse hepatitis virus-induced demyelinating encephalomyelitis

Inborn resistance of mice to myxoviruses: macrophages express phenotype in vitro

) alpha-Synuclein fi laments bind the transcriptional regulator HMGB-1

The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease

IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1

MicroRNA-155 negatively affects blood-brain barrier function during neuroinfl ammation

Leptin as a proinfl ammatory cytokine

Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide

Sex differences in Parkinson's disease

Current and past Epstein-Barr virus infection in risk of initial CNS demyelination

Immune cell migration in infl ammation: present and future therapeutic targets

Antiinfl ammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent

IFN-inducible GTPases and immunity to intracellular pathogens

Central nervous system activation of the indoleamine-2,3-dioxygenase pathway in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis

Deleterious role of IFN{gamma} in a toxic model of central nervous system demyelination

A role for geranylgeranylation in interleukin-1beta secretion

Leptin inhibits apoptosis in thymus through a Janus kinase-2-independent, insulin receptor substrate-1/phosphatidylinositol-3 kinase-dependent pathway

Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma herpesvirus

SeXX matters in immunity

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

Sphingosine-1 phosphate and central nervous system

Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis

Statins reduce dengue virus production via decreased virion assembly

Acute postoperative shingles after thoracic sympathectomy for hyperhidrosis

Balancing susceptibility to infection and autoimmunity: a role for leptin?

Morphological features of Murray valley encephalitis virus infection in the central nervous system of Swiss mice

Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming

Viral manipulation of cellular protein conjugation pathways: the SUMO lesson

Dendritic cells in infl ammatory responses in the CNS

The effect of bovine lactoferrin and lactoferricin B on the ability of feline calicivirus (a norovirus surrogate) and poliovirus to infect cell cultures

Viruses selectively upregulate Tolllike receptors in the central nervous system

Cannabidiol provides long-lasting protection against the deleterious effects of infl ammation in a viral model of multiple sclerosis: a role for A2A receptors

Complement activation is required for induction of a protective antibody response against West Nile virus infection

Simvastatin modulates cellular components in infl uenza A virus-infected cells

Role of lipid modifi cations in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated

JCV agnoproteininduced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons

Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis

The synthetic cannabinoid WIN 55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells following Theiler's virus infection

A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules

Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes

Innate immunity: involvement of new neuropeptides

Consequences of the crosstalk between monocytes/macrophages and natural killer cells

Defi ning the chemokine basis for leukocyte recruitment during viral encephalitis

Dendritic cell dysregulation during HIV-1 infection

The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIVassociated dementia, Alzheimer disease, and multiple sclerosis

Activation of the phagocyte NADPH oxidase by Rac Guanine nucleotide exchange factors in conjunction with ATP and nucleoside diphosphate kinase

Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor

N-Acetyl-cysteine inhibition of encephalomyelitis Theiler's virus-induced nitric oxide and tumour necrosis factor-alpha production by murine astrocyte cultures

Vasculitis of the central nervous system

New perspectives on aspirin and the endogenous control of acute infl ammatory resolution

Macrophage IL-12p70 signaling prevents HSV-1-induced CNS autoimmunity triggered by autoaggressive CD4+ Tregs

Anti-infl ammatory treatment in schizophrenia

Shattuck lecture. Nitric oxide and cyclic GMP in cell signaling and drug development

Production of nitric oxide by glial cells: regulation and potential roles in the CNS

Interferons, signal transduction pathways, and the central nervous system

HIV-1 coat protein gp120 decreases NO-dependent cyclic GMP accumulation in rat brain astroglia by increasing cyclic GMP phosphodiesterase activity

TLR7 is a key regulator of innate immunity against Japanese encephalitis virus infection

Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles

Flaviviruses are neurotropic, but how do they invade the CNS?

The antiviral activities of tetherin

Counteraction of tetherin antiviral activity by two closely related SIVs differing by the presence of a Vpu gene

How viruses hijack the ERAD tuning machinery

The role of AEG-1/MTDH/LYRIC in the pathogenesis of central nervous system disease

Anti-infl ammatory properties of cytochrome P450 epoxygenase-derived eicosanoids

Cannabinoid receptor agonists enhance syncytia formation in MT-2 cells infected with cell free HIV-1MN

Further characterization of high mobility group box 1 (HMGB1) as a proinfl ammatory cytokine: central nervous system effects

Role of IDO activation in anti-microbial defense in human native astrocytes

The role of leukotrienes in airway infl ammation

Epstein-Barr virusassociated primary central nervous system cytotoxic T-cell lymphoma

Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs

The innate immune response affects the development of the autoimmune response in Theiler's virus-induced demyelinating disease

Antiviral innate immunity and stress granule responses

Interferons in the central nervous system: a few instruments play many tunes

Induction of selected chemokines in glial cells infected with Theiler's virus

Infection with Theiler's murine encephalomyelitis virus directly induces proinfl ammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease

IFNgamma is required for viral clearance from central nervous system oligodendroglia

Human adenovirus 36 induces adiposity, increases insulin sensitivity, and alters hypothalamic monoamines in rats

Simvastatin suppresses LPS-induced Akt phosphorylation in the human monocyte cell line THP-1

Manipulation of cellular processing bodies and their constituents by viruses

Interferon-induced proteins with tetratricopeptide repeats 1 and 2 are cellular factors that limit hepatitis B virus replication

IL-6, A1 and A2aR: a crosstalk that modulates BDNF and induces neuroprotection

Virus signaling and apoptosis in the central nervous system infection

Review of 3200 serially received CSF samples submitted for typespecifi c HSV detection by PCR in the reference laboratory setting

An unexpected role for hypoxic response: oxygenation and infl ammation

Intrathecal humoral immunity to encephalitic RNA viruses

Administration of vaccinia virus complement control protein shows signifi cant cognitive improvement in a mild injury model

Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors

Prolongation of survival in retrovirally induced T cell lymphoma by dietary omega 6 fatty acid

Failure of atorvastatin to modulate CSF HIV-1 infection: results of a pilot study

A neuropeptide in immune-mediated infl ammation, Y?

Vascular endothelial growth factor (VEGF) modulates vascular permeability and infl ammation in rat brain

Potential control of multiple sclerosis by cannabis and the endocannabinoid system

Immune markers associated with host susceptibility to infection with West Nile virus

A new treatment for neurogenic infl ammation caused by EV71 with CR2-targeted complement inhibitor

Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology

Peroxisome proliferator-activated receptor alpha antagonism inhibits hepatitis C virus replication

Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and infl ammation

MITA/STING: a central and multifaceted mediator in innate immune response

Omega-3 fatty acids as coadjuvant treatment in AIDS

Pro-resolving lipid mediators (SPMs) and their actions in regulating miRNA in novel resolution circuits in infl ammation

Aerosol exposure to western equine encephalitis virus causes fever and encephalitis in cynomolgus macaques

Type I and III interferon production in response to RNA viruses

Cannabinoids and viral infections

Does nitric oxide play a critical role in viral infections?

Differential regulation of innate and adaptive immune responses in viral encephalitis

Biological interactions between herpesviruses and cyclooxygenase enzymes

Rho GTPases, statins, and nitric oxide

Zinc homeostasis and immunity

Tick-borne fl aviviruses antagonize both IRF-1 and type I IFN signaling to inhibit dendritic cell function

Upregulation of COX-2 and CGRP expression in resident cells of the Borna disease virusinfected brain is dependent upon infl ammation

RAGE: a journey from the complications of diabetes to disorders of the nervous system-striking a fi ne balance between injury and repair

Intrinsic innate immunity fails to control herpes simplex virus and vesicular stomatitis virus replication in sensory neurons and fi broblasts

Inhibition of dengue NS2B-NS3 protease and viral replication in Vero cells by recombinant retrocyclin-1

Farnesylation of Ras is important for the interaction with phosphoinositide 3-kinase gamma

Theiler's virus induces the MIP-2 chemokine (CXCL2) in astrocytes from genetically susceptible but not from resistant mouse strains

Neural stem cell depletion and CNS developmental defects after enteroviral infection

Immune reconstitution infl ammatory syndrome of the brain: case illustrations of a challenging entity

The role of pro-resolution lipid mediators in infectious disease

Sindbis virus translation is inhibited by a PKR/RNase L-independent effector induced by alpha/beta interferon priming of dendritic cells

TLR signaling controls lethal encephalitis in WNV-infected brain

Cannabinoids: novel medicines for the treatment of Huntington's disease

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Oxidative stress-induced assembly of PML nuclear bodies controls sumoylation of partner proteins

Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis

Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46

New agents promote neuroprotection in Parkinson's disease models

Interferon-induced tetherin restricts vesicular stomatitis virus release in neurons

Counteraction of the multifunctional restriction factor tetherin

Adenosine in the spinal cord and periphery: release and regulation of pain

Neutrophilic defensins penetrate the blood-brain barrier

HIV-1 Vpu blocks recycling and biosynthetic transport of the intrinsic immunity factor CD317/tetherin to overcome the virion release restriction

Interferon-stimulated genes: a complex web of host defenses

Measles virus interactions with cellular receptors: consequences for viral pathogenesis

Pan-viral specifi city of IFN-induced genes reveals new roles for cGAS in innate immunity

Astrocytes as targets for Venezuelan equine encephalitis virus infection

Common properties of nuclear body protein SP100 and TIF1alpha chromatin factor: role of SUMO modifi cation

Oxidative damage in dengue fever

Involvement of bovine lactoferrin moieties in the inhibition of herpes simplex virus type 1 infection

Lipoxins and aspirin-triggered 15-epi-lipoxins are the fi rst lipid mediators of endogenous anti-infl ammation and resolution

Novel omega-3-derived local mediators in anti-infl ammation and resolution

Adaptation of human and simian immunodefi ciency viruses for resistance to tetherin/BST-2

Infl ammatory disease as chronic stress

Adeno-associated viralvector-mediated hypoxia-inducible vascular endothelial growth factor gene expression attenuates ischemic brain injury after focal cerebral ischemia in mice

Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology

Effects of pioglitazone on diffusion tensor imaging indices in multiple sclerosis patients

Subtractive expression cloning reveals high expression of CD46 at the blood-brain barrier

Experimental research on nitric oxide and the therapy of Alzheimer disease: a challenging bridge

Immune modulation of the hypothalamicpituitary-adrenal (HPA) axis during viral infection

TRIM5alpha and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment

Mast cells, glia and neuroinfl ammation: partners in crime?

A new paradigm: innate immune sensing of viruses via the unfolded protein response

Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3

Prospects for cannabinoid therapies in viral encephalitis

Activation of tumor suppressor protein p53 is required for Theiler's murine encephalomyelitis virus-induced apoptosis in M1-D macrophages

The effects of neurotrophins and the neuropeptides VIP and PACAP on HIV-1 infection: histories with opposite ends

Complement synthesis and activation in the brain of SIV-infected monkeys

Phosphorylation of vasodilator-stimulated phosphoprotein: a consequence of nitric oxide-and cGMP-mediated signal transduction in brain capillary endothelial cells and astrocytes

Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinfl ammatory cytokine responses induced during VSV encephalitis

The role and regulation of COX-2 during viral infection

Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial

Toll-like receptors in CNS viral infections

Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles

Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2

Selective autophagy and viruses

Involvement of MAPK/ NF-kappaB signaling in the activation of the cholinergic anti-infl ammatory pathway in experimental colitis by chronic vagus nerve stimulation

Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone

Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STINGmediated apoptosis

The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile virus pathogenesis

The interferoninducible gene viperin restricts West Nile virus pathogenesis

The role of autophagy during coxsackievirus infection of neural progenitor and stem cells

Lipidomic profi ling of infl uenza infection identifi es mediators that induce and resolve infl ammation

Near death experiences: poxvirus regulation of apoptotic death

Recent advances in understanding viral evasion of type I interferon

New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1

TRIM79alpha, an interferon-stimulated gene product, restricts tick-borne encephalitis virus replication by degrading the viral RNA polymerase

Age-dependent myeloid dendritic cell responses mediate resistance to La Crosse virus induced neurological disease

Chemical sympathectomy increases susceptibility to ocular herpes simplex virus type 1 infection

Autophagy mediates transporter associated with antigen processingindependent presentation of viral epitopes through MHC class I pathway

Small molecule glutaminase inhibitors block glutamate release from stimulated microglia

Interferon Gamma Inducible protein (IFI)16 transcriptionally regulates type I interferons and other interferon stimulated genes and controls the interferon response to both DNA and RNA viruses

Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir

MicroRNA-29b modulates Japanese encephalitis virus-induced microglia activation by targeting tumor necrosis factor alphainduced protein 3

MicroRNA 155 regulates Japanese encephalitis virus-induced infl ammatory response by targeting Src homology 2-containing inositol phosphatase 1

Enhancement of hepatitis B virus replication by androgen and its receptor in mice

Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinfl ammation and oxidative stress

Physiology and immunology of the cholinergic antiinfl ammatory pathway

Functional characterization of new allelic polymorphisms identifi ed in the promoter region of the human MxA gene

Circulating levels of HMGB1 are correlated strongly with MD2 in HIV-infection: possible implication for TLR4-signalling and chronic immune activation

Biological role of Toll-like receptor-4 in the brain

VSV replication in neurons is inhibited by type I IFN at multiple stages of infection

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

EV71 induces COX-2 expression via c-Src/ PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes

Coupling between cyclooxygenases and terminal prostanoid synthases

ISG12 is a critical modulator of innate immune responses in murine models of sepsis

Immune control by endocannabinoids-new mechanisms of neuroprotection?

Roles of prostanoids revealed from studies using mice lacking specifi c prostanoid receptors

Human lactoferrin but not lysozyme neutralizes HSV-1 and inhibits HSV-1 replication and cell-to-cell spread

Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages

Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy

Translational resistance of late alphavirus mRNA to eIF2alpha phosphorylation: a strategy to overcome the antiviral effect of protein kinase PKR

Acquisition and long-term retention of spatial learning in the human immunodefi ciency virus-1 transgenic rat: effects of repeated nicotine treatment

Virus budding and the ESCRT pathway

Antiviral activity of human lactoferrin: inhibition of alphavirus interaction with heparan sulfate

Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation

Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells

Infl ammasomes in the CNS

Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis

Database-guided discovery of potent peptides to combat HIV-1 or superbugs

Human antimicrobial peptides and proteins

Potential role of high mobility group box 1 in viral infectious diseases

Role of the blood-brain barrier in rabies virus infection and protection

UV light selectively inhibits spinal cord infl ammation and demyelination in experimental autoimmune encephalomyelitis

RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

The pain of being sick: implications of immune-to-brain communication for understanding pain

Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local anti-viral response

Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefi t of atorvastatin in treatment of central nervous system autoimmunity

Contributions of E1A to mouse adenovirus type 1 pathogenesis following intranasal inoculation

Immunotherapy of cancer by IL-12-based cytokine combinations

The effects of restraint stress on the neuropathogenesis of Theiler's virus infection II: NK cell function and cytokine levels in acute disease

Expression of interferon gamma in the brain of cats with natural Borna disease virus infection

A gender gap in autoimmunity

Higher serum testosterone is associated with increased risk of advanced hepatitis C-related liver disease in males

Defensins and viral infection: dispelling common misconceptions

Bacteria, viruses, and hypothalamic infl ammation: potential new players in obesity

The role of sphingosine-1-phosphate in endothelial barrier function

Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS

Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system

Do beta-defensins and other antimicrobial peptides play a role in neuroimmune function and neurodegeneration?

Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders

Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

Immune modulation by estrogens: role in CNS HIV-1 infection

Antiviral mechanisms of human defensins

Interaction of rabies virus P-protein with STAT proteins is critical to lethal rabies disease

Vitamin D in infl ammatory diseases

An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo

Omega-3 fatty acid improves the clinical outcome of hepatectomized patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma

Structural basis for dsRNA recognition, fi lament formation, and antiviral signal activation by MDA5

RIG-G as a key mediator of the antiproliferative activity of interferonrelated pathways through enhancing p21 and p27 proteins

PIN: a novel protein involved in IFN-gamma accumulation of NOS-1 in neurons

PIN: a novel protein involved in IFN-gamma accumulation of NOS-1 in neurons

Pattern recognition receptorinitiated innate antiviral response in mouse adipose cells

Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2

Herpes simplex virus 1 counteracts tetherin restriction via its virion host shutoff activity

T-cell differentiation factor CBF-beta regulates HIV-1 Vif-mediated evasion of host restriction

Leptin mediates the pathogenesis of severe 2009 pandemic infl uenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity

IFIT5 potentiates anti-viral response through enhancing innate immune signaling pathways

NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING

Progress and investigation of neuronal plasticity interfered by Borna disease virus infection

Innate immune response gene expression profi les in central nervous system of mice infected with rabies virus

Inhibition of Epstein-Barr virus infection by lactoferrin

Neutrophils promote mononuclear cell infi ltration during viral-induced encephalitis

Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent infl ammatory responses

Varicella-zoster virus immediate-early protein ORF61 abrogates the IRF3-mediated innate immune response through degradation of activated IRF3

The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffi c and stabilizing the viral capsid

Defense against HSV-1 in a murine model is mediated by iNOS and orchestrated by the activation of TLR2 and TLR9 in trigeminal ganglia