Schizophrenia pathogens

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Relationships between schizophrenia susceptibility genes and certain of the pathogens implicated in the disease

Many of the genes implicated in schizophrenia are also involved in the life-cycles of the pathogens implicated in the disease. These table sumarise some of these interactions.

For further details, see:- Carter C.J. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and T.Gondii. Schiz Bull, in press

Pathogen	Genes implicated in life cycle, affecting, or affected by pathogen
Influenza	ACE, AGA, AKT1, CALR, CCR5, CHN2, CTLA4, DLG2, EGR2, ENTH, ERBB4, FOXP2, GAD1, GALNT7, GCLC, GCLM, GRIN2B, GSTM1, GSTT1, HLA-B, HLA-DRB1, HOMER1, hsa-mir-198, HSPA1B, IL10, IL18, IL1B, IL1RN, IL2, IL4, KPNA3, LTA, MDR1,MICB, NOS1, PI4KA, PIK3C3, PIP5K2A, PLA2G4A, PLA2G4B, PLA2G4C, PLP1, PNPO, PTGS2, RANBP5, RELN, RGS4, SOD2,ST8SIA2, TNF, TPP2, ZNF74
Cytomegalovirus	AKT1, ATF4, B3GAT1, CALR, EGF, EGFR, GCLC, GCLM, GRIN1, GSTM1, GSTT1, HLA-B , HLA-DRB1, HSPA1B, HSPA1L, IL10 ,IL10RA,IL12, IL12B , IL18 , IL18R1, IL18RAP, IL1B, IL1RN, IL2, IL4, KPNA3, LTA, MAG, MICB, MOG, NCAM1, PLA2G4A, PLA2G4B, PLA2G4C, PTGS2.RANBP5, ST8SIA2, TH, TNF, TP53, TPH, TYR, XBP1, ZNF74
HSV-1	ADCYAP1, AKT1, APC, APOE, ATF4, CALR, CCR5, CHRNA7, CNP, CTLA4, EGR2, ERBB2, FGFR1, FYN, GALNT7, GCLC, GCLM, GNAS, GRIN1, GRIN2A, GRIN2B, GRIN2D, GSTM1, GSTT1, HLA-B, HOMER1, HTR2A, IL10, IL12, IL18, IL18RAP, IL1B, IL1RN, IL2, IL4, KPNB3, LTA, MED12, MICB, NOS1, NPY, NTF3, PCQAP, PICK1, PIK3C3, PLP1, PTGS2, SLC1A2, ST8SIA2, TH, TNF, TP53, TYR, ZNF74
Rubella	AGA, AKT1, ATXN1, CALR, CHI3L1, EGFR, EGR3, ENTH, ERBB2, GAD1, GRM3, HLA-A, HLA-B, HLA-DRB1, HOMER1, hsa-mir-198,IL10, MOG, NRG1, PDE4B, PLA2G4A, PLA2G4B, PLA2G4C, PLP1, PLXNA2, PRODH, PTGS2, RBP1, RGS4, SOD2, TP53
B.Burgdorferi	In progress
T.Gondii	ACE, AKT1, CCR5, CTLA4, DRD2, GCLC, GCLM, GNPAT, GSTM1, GSTT1, HLA-B, HLADRB1, HP, HSPA1B, IL10, IL12, IL1B, IL2, IL3,IL4, LTA, MDR1, NCAM1, NOS1, NQO2, NRG2, PAX6, PDE4B, PIK3C3, PNPO, PTGS2, SLC6A3, SOD2, ST8SIA2, TF, TNF, TPH1, UCP2.YWHAH

Pathogen receptors: Pathogens bind to cell surface constituents (sialic acids, phospholipids etc) or to

specific receptorswhich are then internalised using the endocytic pathway

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
AGA aspartylglucosaminidase N-glycan degradation `N4-(beta-N-acetyl-D-glucosaminyl)-L-asparagine + H2O =` `N-acetyl-beta-D-glucosaminylamine + L-aspartate`	Influenza virus infection of CHO cells is redced by N-glycan degradation suggesting that an N-linkedglycoprotein is necessary for entry into cells. This enzyme has not been specifically examined ¹	NF	NF	Beta-N-acetylglucoseamine residues may contribute to a complex Rubella receptor in Vero cells ^2,2	The surface of Borrelia burgdorferi is also coated with N-acetyl-D-glucosamine or galactoseamine residues ³	NF
B3GAT1 beta-1,3-glucuronyltransferase 1 (Synthesises HNK-1)	NF	CMV binds to sulfated glucuronyl glycosphingolipids (B3GAT1 plays a role in their synthesis). An HNK-1 antibody inhibits the pathogenic effects (plaque formation) of CMV ⁴	NF	NF	NF	NF
GALNT7 O-glycan biosynthesis `UDP-N-acetyl-D-galactosamine + polypeptide = UDP +` `N-acetyl-D-galactosaminyl-polypeptide`	Acetylated galactosamine is a receptor for the influenza C virus glycoprotein ⁵	NF	Glycoprotein C of the Herpes virus accquires N-acetylgalactosamine prior to routing to the host golgi apparatus ⁶	NF	The surface of Borrelia is coated with host-derived glycoconjugates containing O-glycosidically linked N-acetyl-D-galactosamine (GalNAc) and N-glycosidically linked N-acetyl-D-glucosamine (GlcNAc) ^3,3.	T. gondii Glycosyl-phosphatidylinositols with a glucose-N-acetylgalactosamine side branch are immunogenic in humans. This structure is widely distributed among T. gondii isolates ⁷.
ST8SIA2 (SIAT8B) ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 Glycan biosynthesis and metabolism: Ganglioside biosynythesis	Alpha-2-6 and alpha-2-3-linked sialic acids are the predominant receptors for the Hemagglutinin molecule ⁸.Alpha-2-8 linked sialic acid binding has also been observed ⁹	CMV binds to sialic acids and infectivity is reduced by sialidase. Specific isoforms have not been examined ¹⁰.	Sialic acid residues bind to envelope glycoproteins of HSV-1. Sialic acid is required for viral entry ¹¹. SIAT8B not specifically examined	NF	NF	Sialic acid residues on the host cell surface are important for parasitic entry. ¹². Alpha-2-3, 2-6 and 2-8 sialylated residues are preferred for the binding of the T.Gondii micronemal protein MIC1¹³
EGF Epidermal growth factor	NF	The EGF receptor is used by the virus for entry and EGFR/ERBB3 heterodimers bind glycobrotein B of the virus ¹⁴ . EGF infusion in mice increases cerebral infectivity in adult mice ¹⁵	NF	Rubella infection causes a decrease in reponsiveness of human embryonic mesenchymal cells to EGF ¹⁶	NF	NF
EGFR	NF	The EGF receptor is used by the virus for entry and EGFR/ERBB3 heterodimers bind glycobrotein B of the virus ¹⁴	ICP0, an HSV-1 protein forms a complex with CIN85 and CBL and increases degradation of the EGF receptor ¹⁷ As the ubiquitin ligase CBL also regulates the degradatuion of ERBB tyrosine kinases ¹⁸, this mechanism may be more general .	Expression increased by rubella infection of human embryo fibroblasts Adamo et al, 2008	NF	NF
FGFR1	NF	NF	Receptor for HSV-1 ¹⁹	NF	NF	NF
IL10RA Interleukin 10 receptor	NF	CMV homolog of IL10 binds to IL10RA²⁰	NF	NF	NF	NF
IMPA2 inositol(myo)-1(or 4)-monophosphatase 2	NF	NF	NF	Several phospholipids (phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylcholine, sphingomyelin) and glycolipids (gangliosides, lactosylceramide, cerebroside sulphate) are able to neutralise infection of Vero cells, suggesting a complex lipid moiety in the cell surface receptor for the virus	NF	NF
PLA2G4A (B and C) phospholipase A2, group IVA (Cytosolic, calcium-dependent)	Infection increases cytosolic phospholipase A2 phosphorylation in epithelial cells ²¹.	Cytomegalovirus infection of smooth muscle or LU cells increases cytosolic PLA2 activity ^22,23 . The virus also adsorbs host cytosolic PLA2. PLA2 inhibitors do not affect cell entry but decrease the expression of cellular viral proteins ²⁴	NF	The rubella virus is believed to bind to membrane phospholipds and glycolipids Phospholipase A2 digestion of Vero cells cells markedly reduces viral infectivity. ². Expression of PLA2G4A increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	T.Gondii possesses calcium-dependent and independent phospholipase A2 which play a role in cell penetration^25,26 . Host phospholipase A2 is also activated by the parasite in macrophages ²⁷ . PLA2 inhibitors reduce T.Gondii infection of THP1 monocytic cells ²⁸.
PSAP Prosaposin	NF	NF	NF	NF	Saposins activate the degradation of galactosylceramide in cells ²⁹. B.Burgdorferi binds to galactosylceramide ³⁰	NF

Adhesion molecules, extracellular matrix, junctions and related

	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
ARVCF armadillo repeat gene deleted in velocardiofacial syndrome	NF	NF	ARVCF is a component of adherens junctions ^31,32which play an important role in the invasion of several viruses including Herpes simplex ³³, Hepatitis B ³⁴, Coxsackie and group C adenoviruses³⁵.	NF	NF	NF
CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39) Alias : GP39, HC-gp39, HCGP-3P, YKL40, YYL-40	NF : Enhances bacterial adhesion and invasion in colonic epithelial cells ³⁶	NF	NF	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
CLDN5 Claudin 5 Tight junction protein involved in blood-brain barrier regulation	NF:Other claudins (1,6 and 9) function as entry receptors for hepatitis C ^37,38.	NF	NF	NF	NF	NF
CNTNAP2 Contactin associated protein-like 2	NF	NF	NF		NF	NF
GJA8 gap junction protein, alpha 8, 50kDa connexin 50	NF	NF	Gap junctions can play a role in herpes transfer between epithelial cells ³⁹. This particular form has not been studied.	NF	NF	NF
NPTN neuroplastin	NF	NF	NF	NF	NF	NF
CHL1 cell adhesion molecule with homology to L1CAM (close homolog of L1)	NF	NF	NF	NF	NF	NF
CHN2 Chimerin (chimaerin) 2	Upregulated in neocortex at postnatal days 35/36 following prenatal influemza infection in mice⁴⁰	NF	NF	NF	NF	NF
NCAM1 Neural cell adhesion molecule 1	NF	Infection downregulates expression in neuroblastoma cells ⁴¹	NF (but receptor for rabies virus)⁴²	NF	Expression downregulated by infection of synovial cells ⁴³. B.Burgdorferi possesses receptors for host plasminogen, which, once bound to the spirochete is converted to active plasmin by the host plasminogen activator uPa (PLAU). Plasmin-coated borrelia degrades components of the extracellular matrix (fibronectin, lamininin, and vitronectin) and this system is used by the parasite to gain entry to cells ⁴⁴. In the brain, relevant substrates for Plasmin include phosphacan (PTPRZ1) ⁴⁵(a tyrosine phosphatase implicated in NRG1/ERBB4 signaling) ⁴⁶and the adhesion molecule NCAM1 ⁴⁷. Plasmin also converts pro-BDNF to BDNF ⁴⁸.	Adhesion molecules play an important role in cell entry
TNXB: tenascin XB	NF	NF	NF	NF	NF	NF

Traffic

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
CALR Calreticulin	Involved in the folding of influenza proteins ^49,50	Glycoprotein B of HSV-1 or cytomegalovirus binds to calreticulin which is involved in the folding of viral proteins ⁵¹	Glycoprotein B of HSV-1 or cytomegalovirus binds to calreticulin which is involved in the folding of viral proteins ^51,52	Rubella glycoproteins E1 and E2 bind to calreticulin ⁵³	NF	NF
DTNBP1 Dysbindin	Many pathogens exploit the trafficking networks used by the cell to obtain nutrients, or to endoctose membrane receptors. These endosomal and other pathways converge on lysozymes, which are able to kill pathogens ⁵⁴. Although dysbindin (DTNBP1), BLOC1S3 or MUTED have not been specifically implicated in viral traffic, they are part of the biogenesis of lysosomal organelles complex (BLOC-1) which is specifically involved in the sorting of cargoes from vacuolar early endosomes to the lysosomal complex ⁵⁵. The BLOC-1 complex is also involved in the transport of melanosome constituents from endosomes to melanosomes. The Varicella Zoster virus is believed to follow this route during infection of melanocytes ⁵⁶.				NF	NF
BLOC1S3 biogenesis of lysosome-related organelles complex-1, subunit 3					-	-
MUTED Muted homolog					-	-
ENTH Epsin 4	Involved in clathrin-mediated endocytosis ⁵⁷ an entry strategy used by Cytomegalovirus ⁵⁸, Herpes simplex ⁵⁹, Influenza ⁶⁰and Rubella ⁶¹				NF	NF
DISC1 Disrupted in schizophrenia 1	Viruses use the microtubule network to gain access to the nucleus and are driven along by the host’s dynein and kinesin motors towards the microtubule organising centre close to the nucleus ⁶². Viral inclusions, factories for viral replication, form at pericentriolar sites close to this microtubule organizing center or in specialized nuclear domains known as ND10/PML bodies ⁶³. DISC1 is a component of this microtubule-related dynein motor complex ⁶⁴ and implicated in centriolar function via its association with kendrin, a binding partner of PCN1 ⁶⁵ A number of DISC1 binding partners ⁶⁶are involved in viral life cycles. For example FEZ1 binds to the JC virus agnoprotein ⁶⁷, citron kinase (CIT) binds to the P90 protein of the rubella virus ⁶⁸, while TUBB2A binds to the influenza virus ribonucleoprotein complex⁶⁹.				NF	NF
FEZ1	NF Binds to agnoprotein of human polyomavirus JC virus (JCV) (causes demyelinating disease) ⁶⁷	NF	NF	NF	NF	NF
PCM1 pericentriolar material 1	NF : viral inclusions, factories for viral replication form at pericentriolar sites close to the microtubule organizing center or in specialized nuclear domains known as ND10/PML bodies ⁶³.				NF	NF
KPNA3 karyopherin alpha 3 (importin alpha 4)	Nuclear transport: Involved in the nuclear import of Influenza viral nucleoprotein ⁷⁰	The importin alpha/beta pathway is reqired for nuclear import of the virus, a component of which UL84) binds to KPNA1,4 and 5 and IPO1⁷¹	NF	NF	NF	NF
KPNB3 (RANBP5)	Nuclear transport : Important role in the nuclear import of Influenza viral RNA polymerase ⁷²	See above	Beta importins play an important role in the binding of HSV-1 capsids to the nuclear membrane ⁷³	NF	NF	NF
KIF2A kinesin heavy chain member 2A	Kinesins transport viruses along microtubules including influenza components (role of KIFC3 demonstrated) ⁷⁴	NF	Kinesins transport HSV-1 along microtubules to the nucleus ⁷⁵. Viral proteins bind to KIF1A ⁷⁶ and uKHC kinesin heavy chain ⁷⁷. KIF2A not specifically examined	NF	NF	NF
NDE1 LIS1-interacting protein NUDE1	NF	NF	NF	NF	NF	NF
PIK3C2G phosphoinositide-3-kinase, class 2, gamma polypeptide	NF	NF	NF	NF	NF	NF
PIK3C3 phosphoinositide-3-kinase, class 3 (vps34)	This particular PI kinase vps34 is involved specifically in the vacuolar protein sorting pathway which is one used by the virus to gain entry to cells. Transfection of a dominant-negative PIK3C3 blocks virus particles in endosomes ⁷⁸.	NF	Down regulated by HSV-1 infection of rat fibroblasts ⁷⁹	NF	NF	The parasite survives in macrophages in vacuoles that avoid fusion with lysosomes. Activation of the immune response can reroute these vacuoles to the lysosomal system allowing macrophage bactericidal activity. VPS34 plays a key role in this vacuolar/lysosomal fusion and in enabling macrophages to kill T.gondii ⁸⁰
PI4KA phosphatidylinositol 4-kinase, catalytic, alpha	Involved in the transport of influenza hemagglutinin from the trans-Golgi network (TGN)-to-cell surface ⁸¹	NF	NF	NF	NF	NF
PIP5K2A phosphatidylinositol-4-phosphate 5-kinase, type II, alpha	The Influenza M2 proton channel possesses a phosphatidylinositol 4,5-bisphosphate-binding motif.⁸². PI5 kinases are involved in the intracellular transport of viral hemaglutinin⁸³. This isoform was not specifically examined.	NF	NF	NF	NF	Upregulated by T.Gondii infection of porcine epithelial cells ⁸⁴
MAP6 Microtubule-associated protein 6	Binds to microtubule components including TUBB2A, a binding partner of the influenza viral ribonucleoprotein complex and polymerase complex ⁶⁹	The microtubule network is used to transport the virus to the nucleus ⁸⁵	HSV-1 uses microtubules to travel beween the plasma membrane and the nucleus. MAP6 not specifically examined ^86,87	Microtubule-disrupting drugs inhibit rubella entry to vero cells ⁶¹	NF	T.Gondii forms a vacuole within the host cell, to which it recruits host microtubules. This results in sequestretaion of endo-lysosomes within the vacuole . The lysosomal degradation products may serve as nutrients for the parasite ⁸⁸
TUBA8 tubulin, alpha 8	NF	Microtubules are affected by CMV ^89,90but no specific interactions with this form have been reported.	HSV-1 uses the microtubule network to migrate from the plasma membrane to the nucleus. Interactions with this particular isoform not reported ^91,92.	NF	NF	Host microtubules are affected by parasitic infection and concentrate around the parasitic intracellular vacoule. Specific interactions not identified⁹³.
HSPA1B HSP70-2	Cellular partner of the influenza virus ribonucleoprotein and polymerase complex ⁶⁹	CMV Glycoprotein b binds to grp78/Bip (HSPA5) and grp94 (HSP90B1)⁹⁴. CMV IE2 protein binds to the promoter of hsp70’s including HSPA1A/HSPA1B and HSPA1L ⁹⁵.	NF	NF	Borrelia genes encode for a number of heat shock proteins . Molecular mimicry has been observed for bHSP60 ⁹⁶but not for other ~70kD species ⁹⁷.	T.gondii produces its own HSP70 ^98,99. Autoantibodies can cross react with murine HSP70 producing anaphylactic reaction ^100,101
HSPA1L		CMV Glycoprotein b binds to grp78/Bip (HSPA5) and grp94 (HSP90B1)⁹⁴. CMV IE2 protein binds to the promoter of hsp70’s including HSPA1A/HSPA1B and HSPA1L ⁹⁵.
UFD1L ubiquitin fusion degradation 1 like	NF	UFD1L associates with NPLOC4 and Valosin containing protein VCP (aka cdc48): This complex plays a key role in endoplasmic reticulum associated protein degradation ¹⁰². A cytomegalovirus protein (US2) assistes in the degradation of MHC class 1 and II proteins via this route by recruiting VCP to ER-associated degradation complexes ¹⁰³.	NF	NF	NF	Upregulated by infection of porcine epithelial cells ⁸⁴
XBP1 X-box binding protein 1.	NF: General: Subjugation of the host’s protein folding machinery by viral polypeptides leads to endoplasmic reticulum stress ⁶⁰. ATF6 and XBP1 play a key role in this pathway	Cytomegalovirus infection of fibroblasts induces the unfolded protein reponse characterised by increased splicing of XBP1. Mediated via the CMV protein US11. This enables US11 to divert class I major histocompatibility complex (MHC) heavy chains (HC) from the endoplasmic reticulum (ER) to the cytosol where thay are degraded by the proteasome ¹⁰⁴.	NF	NF	NF	NF

Nutrition

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
GNPAT glyceronephosphate O-acyltransferase	NF	NF	NF	NF	Spirochetes forage phospholipids in the blood. They contain and enzyme (GpsA) that metabolises dihydroxyacetone phosphate (glycerone-3-phospate) to glycerol-3-phosphate that may be used as an energy source by the parasite. GNPAT metabolises glycerone-3-phospate to acylglyceronephosphate.¹⁰⁵	NF
TPH1 Tryptophan hydroxylase	NF	Lack of tryptophan blocks cytomegalovirus replication ¹⁰⁶	NF	NF	NF	Tryptophan is required for T.Gondii growth and the organism displays auxotrophy for tryptophan ^107,108

Viral transcription

RNA polymerase and transcription	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
MED12 mediator of RNA polymerase II transcription, (HOPA)	NF	NF	The multiprotein Mediator complex is a coactivator required for transcriptional activation of RNA polymerase II transcribed genes by DNA binding transcription factors. This complex is used by Herpes simplex which diverts the host RNA polymerase towards viral RNA synthesis, A viral protein VP16 binds to components of the mediator complex (MED 17 and 25¹⁰⁹	NF	NF	NF
PCQAP (ARC105) MED15 may Transcriptional coactivator in RNA polymerase II transcription	NF	NF	Binds to the herpes viral protein VP16¹¹⁰	NF	NF	NF
ZNF74 zinc finger protein 74 (Cos52) ZNF74 binds to hyper- but not hypo-phosphorylated RNA polymerase II (POL2RA)¹¹¹	RNA polymerase II is recruited by the virus for transcription¹¹²	Cytomegalovirus induces hyperphosphorylation of RNA polymerase II. Mediated by a viral kinase (UL97) ^113,114 A further viral protein (IE86) blocks assembly of RNA polymerase with the preinitiation complex ¹¹⁵. ZNF74 Binds to hyper- but not hypo-phosphorylated RNA polymerase II (POL2RA)¹¹¹	RNA polymerase II is recruited by Herpes simplex to transcribe viral genes ¹¹⁶. It is phosphorylated by a complex of CDK9 and a viral protein (ICP22)¹¹⁷	NF	NF	NF
PNPO	Pyridoxal 5 phosphate (Vitamin B6) , a product of this enzyme inhibits the influenza virus transcriptase ¹¹⁸	NF	NF	NF	NF	Protein downregulated by T.Gondii fibroblast infection ¹¹⁹

Viral DNA/RNA Methylation

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
MTR 5-methyltetrahydrofolate-homocysteine methyltransferase 5-methyltetrahydrofolate + L-homocysteine = tetrahydrofolate + L-methionine	Viral RNA methylation, using the methyl donor S-adenosylmethionine is crucial for the maturaton of viral RNA (See Declerq ¹²⁰). The product of these methylation reactions, S-adenosylhomocysteine inhibits the diverse methyltransferases involved in this process¹²⁰. S-adenosylhomocysteine (SAH) is normally rapidly metabolised to adenosine and homocysteine by SAH hydrolase (ADCY) and inhibitors of this enzyme inhibit viral RNA methylation by favouring SAH accumulation. SAH hydrolase inhibitors display broad-spectrum antiviral activity ¹²⁰. Methyltransferase inhibitors also inhibit influenza viral replication ¹²¹ and methylation inhibition also results in the increased nuclear retention of influenza viral RNA ¹²². Methylation of viral DNA or proteins also plays a role in the viral life cycles. For example, HSV-1 latency or lytic infection can be influenced by such reactions ¹²³. The availability of S-adenosylmethionine is thus a general factor contributing to viral viability. One might also expect that methylation of viral RNA would be a competing factor for the methylation of host DNA or proteins, depending on the compartment in which this occurs. Viruses also affect the methylation of host DNA. For example the herpes simplex strain HSV-2 produces marked hypomethylation of host DNA in infected rat embryo cells, although this effect may be due to a redistribution of the host DNA methyltransferase rather than to any diversion of methionine/homocysteine metabolism towards viral methylation ¹²⁴. A generalised decrease in DNA methylation has been observed in leukocytes isolated from male schizophrenic patients ¹²⁵. Several genes implicated in schizophrenia (MTHFR, MTR and MTHFD1) are relevant to this area . Other methylating enzymes may also influence this cycle indirectly by modifying substrate levels. For example, phosphatidylethanolamine methyltransferase (PEMT) knockout mice have dramatically reduced plasma homocysteine levels ¹²⁶and COMT inhibition increases S-adenosylmethionine levels in the rat brain ¹²⁷.				NF	NF
MTHFD1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase Multifunctional folate metabolism enzyme catalyzing reactions of 1.5.1.5, 1.5.1.15, 3.5.4.9 and 6.3.4.3
MTHFR Methylenetetrahydrofolate reductase 5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate+ NAD(P)H + H+					NF
PEMT phosphatidylethanolamine N-methyltransferase	NF	NF	NF	NF	NF	NF
COMT Catechol-O-methyltransferase	NF	NF	NF	NF	NF	NF

Growth factor signaling: Pathogens may at different stages of their life cycle either inhibit PI3K/AKT signaling resulting in apoptosis, and release of the pathogen, or stimulate this survival pathway, enabling them to stay in residence Apoptosis, Cell Signaling, And Human Diseases: Molecular Mechanisms By Rakesh Srivastava

	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
ALK (anaplastic lymphoma kinase) pleiotrophin receptor	NF	NF	NF	NF	NF	NF
AKT1 v-akt murine thymoma viral oncogene homolog 1	The NS1 viral protein binds to the p85 beta subunit of phosphoinositide kinase (PIK3R2) and activates AKT1 signalling. These effects limit the viral-induced cell death programme allowing further replication ^290,291	Rapidly activated by CMV infection of astroglial and fibroblast cells ²⁹². Used to counter apoptosis ²⁹³.	Activated by infection ²⁹⁴.	Activated by Rubella infection of RK13 cells ²⁹⁵	NF	Activated by T.Gondii infection as part of an anti-apoptotic programme for self-presevation ²⁹⁶
BDNF brain derived neurotrophic factor	NF	Undifferentiated human neural precursor cells support replication of the virus. This property is maintained by treatment favouring the development of the astroglial cell type, but lost by differentiation of the cells to a neuronal cell-type by treatment with BDNF and PDGF ²⁹⁷	NF	NF	NF	NF
FYN FYN oncogene related to SRC, FGR, YES	NF	NF	The ICP0 protein of HSV-1 binds to FYN and other SRC kinases (src, yes, fgr) ²⁹⁸	NF	NF	NF
FGF1	NF	NF	NF	NF	NF	NF
GFRA1 GDNF family receptor alpha 1	NF	NF	GDNF and NTF3 expresion increased by HSV-1 encephalitis in mice ²⁹⁹	NF	NF	NF
NRG1 Neuregulin 1	EBP1 (PA2G4), an ERBB3 binding partner ,dissociates from this receptor and translocates to the nucleus following NRG1 stimulation ³⁰⁰. EBP1 inhibits the influenza virus transcriptase ³⁰¹	NF	NF	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
NRG2	NF	NF	NF	NF	NF	Upregulated by infection of human fibroblasts ²⁸⁸
NRG3 Neuregulin 3	NF	NF	NF	NF	NF	NF
ERBB2	NF	NF	Expression increased by HSV-1 infection of trigeminal ganglia in mice ³⁰²	Expression reduced by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
ERBB4 Neuregulin receptor	Upregulated in the hippocampus postnatally following prenatal infection in mice ²⁵⁶	NF	NF	NF	NF	NF
NTF3 neurotrophin 3	NF	NF	Expresion upregulated by Herpes simplex infection (along with GDNF) ²⁹⁹	NF	NF	NF

Innate Immune system: By definition involved in pathogen defense

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
CCR5 delta32 deletion (late onset)	CCR5 defficicient mica show increased mortality to Influenza infection ¹²⁸	CCR5 polymorphisms modify CMV infection in man ¹²⁹ .Downregulated in immature dendritic cells by CMV infection ¹³⁰ and in monocytes ¹³¹	Expression induced by HSV-1 corneal infection ¹³². Occular infection increased in CCR5 defficient mice. ¹³³	NF	Increased expression in CSF T-calls in neuroborreliosis ¹³⁴	Binds to a cyclophilin-like protein 9C18) secreted by T.Gondii ¹³⁵. The delta32 deletion protects against toxoplasmosis in HIV+ve patients ¹³⁶
CSF2RA colony stimulating factor 2 receptor, alpha, low-affinity (granulocyte-macrophage)	Pretreatment of human monocytes with GMCSF enhances viral protein production and increases viral release and cytotoxicity. Synergistic activation of TNF, IL1B, and IL-6 by the virus and GMCSF may however potentiate the beneficial effects of cytokines on infection ¹³⁸	Cytomegalovirus infection produces a profound depletion of GMCSF or GCSF in HUVEC cells, vascular endothelial cells or bone marrow stromal cells. Such myelosuppression may plat an important role in circumventing host defense ^139,140,141	Systemic recombinant GMCSF protects mice againsts HSV1 infection ¹⁴²	GMCSF is induced by rubella infection of fibroblasts ¹⁴³	Infection stimulates GMCSF production in human monocytes ¹⁴⁴ and dendritic cells ¹⁴⁵. Phagocytosis of the spirochete by monocytes is enhanced by GMCSF ¹⁴⁶. Serum levels of GMCSF are increased in infected patients ¹⁴⁷.	Toxoplasma infection of astroglia releases IL1A, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) . ¹⁴⁸. GM-CSF and granulocyte colony-stimulating factor are secreted by T.Gondii infected fibroblasts and delay neutrophil apoptosis ¹⁴⁹. TNF + GMCSF limit T.Gondii multiplication in HUVEC cells ¹⁵⁰. Covaccination with plasmids coding for antigens specific for T.Gondii and a plasmid containing GMCF provides effective protection against infection in mice ¹⁵¹
CSF2RB	See above	See above	See above	See above	See above	See above
CTLA4 cytotoxic T-lymphocyte-associated protein 4	CTLA4-positive T-cells are elevated by influenza infection, particularly in influenza-related encephalopathy. As CTLA4 represses the T-cell mediated antigen-activated immune response this effect may play a permissive role in infection¹⁵²	NF	CTLA4 immunoglobulin treatment reduces survival in HSV-1 infected mice, an effect related to inhibition of the anti-HSV CD4(+) and CD8(+) T-cell responses and a reduction in T-cell number ¹⁵³	NF	CD4(+) CTLA-4(+) regulatory T cells are increased in early Lyme disease (Borreliosis)¹⁵⁴	Administration of CTLA4-Immunoglobulin to SCID mice infected with T. gondii increases parasite burden ¹⁵⁵.
EGR2 EGR proteins (EGR2,3,4) are induced in T-cells following antigen stimulation where they control the expression of cytokine , growth and apoptosis related genes ¹⁵⁶.	Downregulated in neocortex at postnatal days 35 following prenatal influemza infection in mice ⁴⁰	NF	Binds to HCFC1 a transcriptional cofactor required for activation of herpes simplex virus immediate-early genes by the viral protein VP16 ¹⁵⁷	NF	NF	NF
EGR3 early growth response 3	Negative regulator of T-cell activation ¹⁵⁸	NF	NF	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
EGR4 early growth response 4	See above	NF	NF	NF	NF	NF
IL1B Interleukin 1B	Cytokines including IL1B, TNF, are commonly produced at the sites of influenza infection ¹⁵⁹. IL1B may not be directly involved in viricidal effects but may enhance recovery by recruiting T-cells to the site of infection ¹⁶⁰	Infection increases production and release in monocytes ¹⁶¹ a cmv PROTEIN (IE2) binds to the IL1B promoter ¹⁶²	Induced in brain by HSV encephalitis ¹⁶³. TNF and IL1B induced by infection of murine microglia ¹⁶⁴ CMV can be reactivated by IL4 and other cytokines in myeloid cells ¹⁶⁵. TNF, IL1B and IL4 can activate the CMV intermediate gene promoter ¹⁶⁶	NF	Secreted in response to infection of human peripheral blood mononuclear cells.¹⁶⁷	Induced by infection of neurones with T.Gondii ¹⁶⁸. IL1B inhibits T.Gondii growth and replication in vascular endiothelial and HUVEC cells ^169,170. Systemically administed IL1B or TNF protect mice against T.Gondii infection ¹⁷¹
IL1RN Interleukin 1 receptor antagonist	Systemic injection or recombinant IL1RN increases survival following influenza infection in mice ¹⁷²	IL1RN (variable numbers of 86-bp repeats in intron 2) and TNF polymorphisms (base exchange polymorphism at position -308) modify Cytomegalovirus infectivity ¹⁷³. CMV gene products IE1 downregulates while IE2 upregulates expression ¹⁷⁴	Protects against herpes stromal keratitis ^175,176	NF	Secreted in response to infection of human peripheral blood mononuclear cells, although in lesser quantity than IL1B ¹⁶⁷. Reduced Borrelia induced produxtion of IL8 in human peripheral blood mononuclear cells ¹⁷⁷.	NF
IL2: Interleukin 2	NF. Infection of mouse splenocytes reduces IL2 production and natural killer cell activity ¹⁷⁸.	A cytomegaloviirus intermediate early genes (IE2) activates the IL2 and IL2R promoter and increases their expression. IE2 also attenuates the suppressive effects of cyclosporin A on IL2 expression ^179,180	IL-2 permits viral infectivity of T-lymphocytes and stimulates viral replication in infected cells ¹⁸¹	NF	Reduces Borrelia infection in mice ¹⁸²	T.Gondii Infectious burden is increased in IL2 knockout mice ¹⁸³
IL3 interleukin 3 (colony-stimulating factor, multiple)	NF	NF	Protects mice from HSV-1 infection by promoting interferon production ¹⁸⁴	NF	NF	IL3 and IL6 limit T.Gondii replication in mice microglia . TNF or prolactin kill T.Gondii in microglia, effects accompanied by the release of IL1B, IL3 and IL6. T.Gondii killing is reversed by IL3 or IL6 antibodies¹⁸⁵
IL3RA interleukin 3 receptor, alpha (low affinity)	See above	See above	See above	See above	See above	See above
IL4: Interleukin 4	Delays clearance of the virus in infected mice¹⁸⁶ and increase viral cytotoxicity in cell culture ¹⁸⁷.	Occular infection correlates with periods of high IL4 levels ¹⁸⁸. The ability of CMV to infect human monocytes also shows IL4 dependence ¹⁸⁹. IL4 is produced by T-cells in response to CMV ¹⁹⁰	CMV can be reactivated by IL4 and other cytokines in myeloid cells ¹⁶⁵. TNF, IL1B and IL4 can activate the CMV intermediate gene promoter ¹⁶⁶. IL4 plays a permissive role for CMV infection of monocytes ¹⁸⁹.	NF	IL4 and IFNG levels are increased in the CSF of infected patients ¹⁹¹. IL4 increases resistance to infection in mice ¹⁹²	T.Gondii related mortality is enhanced in IL4 knockout mice, brain damage is increased and more cysts are observed ¹⁹³
LTA Lymphotoxin alpha	CD8 T cell responses to influenza are impaired in LTA knockout mice ^194,195 . Bone marrow B cell apoptosis following viral infection in mediated by TNF and LTA ¹⁹⁶	Natural killer cells release LTA and TNF in response to CMV infection, LTA is involved in the release of interferon beta from infected fibroblasts, which inhibits viral replication ¹⁹⁷	LIGHT and LTA are ligands for the herpes viral entry mediator (HCEM/ TNFRSF14)¹⁹⁸ LTA-deficient mice show enhanced susceptibility to HSV-induced encephalitis ¹⁹⁹	NF	NF	Cerebral infection increased in LTA or TNF knockout mice ²⁰⁰
IL10 Interleukin-10	Plasma levels of IL-6, TNF-alpha, INF-alpha, INF-gamma and IL-10 are increased following influenza infection ²⁰¹	A viral homolog of IL10 binds to IL10RA²⁰ IL10 polymorphisms modify infectivity in man ¹²⁹.	Suppresses chemokine expression induced by HSV-1 corneal ²⁰²or microglia ²⁰³infection. IL10 polymorphisms modify HSV-1 infection in man ²⁰⁴.	Elevated seruum levels following infection ²⁰⁵.	Serum levels increased following infection in children ²⁰⁵	Induced by T.Gondii infection and Involved in the immunosuppression produced by the parasite ²⁰⁶. Increased secretion of TNA and IL10 in infected microglia ¹⁴⁸ . Anti-IL10 antibodies reduce infection in mice ¹⁹³
MICB MHC class I polypeptide-related sequence B	Upregulated in influenza-infected macrophages ²⁰⁷	Binds to the CMV protein UL16 and other « ULBP’s ». CMV infection increases expression of MICA andMICB, ligands for the natural killer cell receptor NKG2D (KLRK1). Activation of this receptor triggers Natural killer cells and costimulates antigen-specific effector CD8 T cells. MICB binding by UL16 may circumvent this immune response ^208,209,210A viral encoded microRNA (UK112) targets and downregulates MICB²¹¹	Polymorphisms in MICB correlate with HSV-1 seropositivity ²¹²	NF	NF	NF
IL12B natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor 2, p40	NF	Suppresses CMV infection ²¹³	HSV1 viral load is decreased by IL12 in mice ²¹⁴	NF	NF	Parasite burden is increased in IL12 knockout mice ²¹⁵
IL18	Viral clearance is enhanced in IL18 defficient mice ²¹⁶. IL18 increases resitance to influenza by increasing natural killer cell activity ²¹⁷.	IL18 activated natural killer cells play a role in defense against CMV ²¹⁸	IL18 protects mice against HSV-1 infection ²¹⁹. Infection increased in IL18 knockout mice. Related to reduced activity of natural killer cells ²²⁰.			IL2 + IL18 protect against T.Gondii infection via activation of natural killer cells ²²¹. IL18 enhances resistance to T.Gondii ²²².
IL18R1	See above
IL18RAP	See above	See above	Associated with HSV-1 seropositivity in schizophrenia cases ²²³.	NF	NF
TNFA: Tumor necrosis factor alpha	One of many cytokines induced by influenza infection ²²⁴. Inhibits interferon alpha release induced by influenza infection of dendritic cells ²²⁵	IL1RN (variable numbers of 86-bp repeats in intron 2) and TNF polymorphisms (base exchange polymorphism at position -308) modify Cytomegalovirus infectivity ¹⁷³ CMV protein UL144 encodes for a TNF receptor mimic that activates nuclear factor kappa B signaling ²²⁶	Can both inhibit and reactivate HSV-1 infection. Inhibits virtal replication in Hep2 cells via induction of IFN beta ²²⁷ but can encance the replication and reactivation in the mouse trigeminal ganglia ²²⁸. TNF and IL1B induced by infection of murine microglia ¹⁶⁴. Mortality to HSV1 encepalitis is increased in TNF knockout mice ²²⁹	NF	Expression and secretion markedly induced by Borrelia infection of macrohages, microglia and astrocytes ^{230,231,232,233}. Infection in mice can be reactivated by TNF antibodies ²³⁴	Host TNF plays an important role in controlling resitance to T.Gondii²³⁵. The parasite retaliates via a number of mechanisms that reduce TNF production induced by several pathwaysincluding MAP kinase NFKB1, Toll-like receptor and STAT3 related networks ^{236,237,238,239}. Cerebral infection increased in LTA or TNF knockout mice ²⁰⁰
HLA-A10	NF: But HLA-A10 in common with Chlamydia Psitacci infection is an important risk factor ²⁴⁰	NF	NF	NF	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF
HLA-B	Viral peptide binds to HLA-B37 ²⁴¹	Polymorphisms modify the T-cell response to cytomegalovirus ²⁴²	HLA-b antigen frequeny related to HSV-1 infection ^243,244	Involved in viral infection and the response to vaccination ^245,246	Expression increased by rubella infection of human embrionic and adult fibroblasts Adamo et al, 2008	Human transgene HLA-B27 is a determinant of T.gondii cyst formation in mice ²⁴⁷
HLA-DRB1 DRB1*04 major histocompatibility complex, class II, DR beta 1	Recognises peptides derived from the influenza virus ^248,249	NF	NF	NF	Recognises peptides derived from the Rubella virus ²⁵⁰	Recognises peptides derived from Borrelia burgdorferi ^251,252
TPP2 Tripeptidyl petidase II	Involved in the antigen processing of the Influenza virus ²⁵³	NF	NF	NF	NF	NF
CNR1 Cannabinoid receptor 1	Delta-9-tetrahydrocannabinol increases viral load in influenza-infected mice ²⁵⁴	NF	Cannabinoids have immunosuppressive properties and delta-9-tetrahydrocannabinol reduces reistance to HSV-2 infection in mice ²⁵⁵	NF	NF
FOXP2 Forkhead box P2	Expression increased in brains of the offspring of influenza-infected mice ²⁵⁶ Forkhead proteins including FOXP2 bind to NFAT , an important regulator of T-cell function ²⁵⁷	NF	NF	NF	NF	NF

Glutathione and oxidative stress

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdorferi	T. Gondii
GCLC and GCLM glutamate-cysteine ligases (glutathione synthase)	Glutathione reduces infectivity in mice ²⁵⁸	Glutathione levels also modify the infectivity of the human cytomegalovirus and endothelial cells naturally containing higher levels of glutathione are more resistant to infection ²⁵⁹	HSV-1 infection of microglia results in the upregulation of the glutamate/cysteine transporter SLC1A2. Buthionine sulfoximide, which inhibits glutathione synthesis, increases the number of HSV-1 infected, cells ²⁶⁰. HSV-1 infection decreases intracellular glutathione levels in Vero cells and glutathione supplementaion markedly inhibits viral replication ²⁶¹. S-acetylglutathione, reduces HSV-1 induced mortality in mice ²⁶².	NF	NF	Glutathione causes parasite egress in infected cells. It activates a T.Gondii secreted apyrase (nucleoside triphosphate hydrolase) in the parasite vacuole resulting in a rapid depletion of host cell ATP ²⁶³
GSTM1 Glutathione transferase M1	NF	NF		NF
HP Haptoglobin	NF	NF	NF	NF	NF	Serum levels increased by infection in mice ²⁶⁴
MDR1/ABCB1 P-glycoprotein 1	Cells overexpressing P-glycoprotein are resistant to Influenza infection . It was suggested that this may apply to other enveloped viruses entering cells by plasma membrane fusion eg Herpes simplex and HIV-1) ²⁶⁵	NF	See Influenza	NF	NF	Expression reduced by T.Gondii infection of cancer cells ²⁶⁶
ME2 malic enzyme 2, NAD(+)-dependent, mitochondrial	NF	NF	NF	NF	NF	NF
NOS1Nitric oxide synthase	Influenza infection in utero increases hippocampal NOS1 expression in neonatal mice ²⁶⁷	No specific relationships with NOS1. Nitric oxide can promote both beneficial and deleterious effects against CMV infection ²⁶⁸	Cerebral expression increased by infectionin mice ²⁶⁹. S-nitrosylation of viral proteins may constitute a host-defense mechanism ²⁷⁰	NF	No specific links with NOS1. Nitric oxide kills Borrelia species ²⁷¹	NO derived from macrophages is toxoplasmacidal ²⁷²
PTGS2 Cyclooxygenase-2	Infection increases expression ²¹.Influenza-induced mortality is reduced in PTGS2 knockout mice although lung viral titers are increased ²⁷³ .	Infection increases PTGS2 expression, an effect linked to increased viral replication ^{274,275,276,277}: PTGS2 inhibitors can inhibit viral replication ^278,279	Activity increased by infection . Cox-2 inhibitors inhibit viral infection and reactivation ²⁸⁰	Expression increased by rubella infection of human embryo fibroblasts Adamo et al, 2008	Expression increased in infected murine microglia ²⁸¹	PTGS2 expression increased in infected cells ²⁸²
SOD2 2 superoxide + 2 H(+) ó O₂ + H₂O₂	Induced by cellular viral infection ^283,284,285. Viral replication reduced by recombinant SOD2 in mice ²⁸⁶	NF	NF	Expression increased by rubella infection of human embryo fibroblasts Adamo et al, 2008	NF. The spirochete produces its own superoxide dismutase ²⁸⁷ Upregulated by T.gondii infection of human fibroblasts ²⁸⁸	The parasite produces its own superoxide dismutase ²⁸⁹ Protein upregulated after T.Gondii infection of fibroblasts ¹¹⁹

Molecular mimicry

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
CHRNA7 Nicotinic receptor alpha subunit	NF	NF	Molecular mimicry between PESDQPDL), and residues [286-293] (PNATQPEL) of nicotinic receptor and [381-388] (PEDDQPSS) of HSV-GpD.	NF	NF	NF
CNP 2’,3’-cyclic nucleotide 3’ phosphodiesterase	Large enveloped DNA viruses including Influenza possess intrinsic cyclic nucleotide phosphodiesterase activity. Viral yield in chick myeloblasts is correlated with cellular CNPase activity suggesting a role of the host and viral enzyme in viral replication ³⁰³.	NF	Elevated CSF activity of CNP in Bell’s palsy patients correlated with HSV-1 seropositivity ³⁰⁴	NF	Molecular mimicry reported between CNP1 and a borrelia antigen ³⁰⁵	Cyclic AMP stimulates T.gondii growth³⁰⁶
GAD1 (GAD67) Glutamate decarboxylase 1	Cerebral exression in neonates increased following infection in utero ³⁰⁷	NF	NF	Molecular mimicry between GAD65or GAD67 and a Rubella antigen in diabetic patients ³⁰⁸	NF	NF
TYR Tyrosinase	NF	Antigenic molecular mimicry has been observed between a cytomegalovirus envelope glycoprotein H peptide and Tyrosinase ³⁰⁹	HSV-1 viral vectors (per se) activate the tyrosinase promoter ³¹⁰	NF	NF	NF
MAG myelin-associated glycoprotein	NF	Cytomegalovirus infection correlates with IgM anti-MAG /antibody levels in neuropathic conditions ³¹¹	NF	NF	NF	NF
MOG myelin oligodendrocyte glycoprotein	NF	Human CMV-UL86 peptide 981-1003 shares a crossreactive T-cell epitope with the MOG peptide 34-56 ³¹²	NF	Rubella virus antibodies induces demyelination in culture, an effect related to moleculalar mimicry betwwen MOG and structural glycoprotein E(2)of the virus ³¹³	NF	NF
PLP1	Expression of PLP1 and MBP is downregulated in newborn mouse brain following maternal influenza infection ³¹⁴	NF	Expresion increased in the trigeminal ganglia follwing reactivation of HSV-1 infection in rabbits ³¹⁵	Rubella infection can produce reactive T-cells generating autoantibodies to myelin basic protein and PLP1³¹⁶	NF	NF

Diverse binding partners and interactions

Gene	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
ACE Angiotensin converting enzyme (synthesises angiotensin II)	Cleaves an influenza antigen nucleoprotein (NP)(147-158R-) ³¹⁷	NF	NF	NF	NF	Serum levels increased by Toxoplasmosis ³¹⁸
ATF4 activating transcription factor 4	NF	Activated by CMV infection ³¹⁹	Binds to the Latency transcript of HSV-1 ³²⁰.
NQO2 NAD(P)H dehydrogenase, quinone 2	NF	NF	NF	NF	NF	Binds to a T.Gondii GRA protein forming a part of the parasparasitophorous vacuole ³²¹
PAX6 paired box gene 6 (aniridia, keratitis)	NF	NF	NF	NF	NF	Binds to GRA3, a T.gondii secreted protein important in the parasitophorous vacuole.³²¹
TF transferrin	NF	NF	NF	NF	Binds to a Borrelia protein ³²²	Binds to T.Gondii proteins ³²³
TP53 tumor protein p53	P53 is upregulated by viral infection and is involved in the apoptotic cell death induced by the virus. Apoptosis in vitro and in vivo is attenuated by p53 knockout which also inhibits viral replication ³²⁴.	HCMV infection induces a rapid stabilisation of p53 which is sequestered by the virus into its replication centres . P53 enables viral replication ³²⁵A viral protein IE2 binds to TP53³²⁶	HSV-1 infection stabilises p53 ³²⁷. RL2 ubiquitin E3 ligase ICP0 binds to TP53 ³²⁸	Involved in Rubella-dependent apoptosis ³²⁹	NF	NF
Hsa-mir-198 Vita database	hsa-mir-198 is predicted to target viral genes encoding for the Influenza virus PB2 protein and for structural proteins E1, E2 and C of the Rubella virus as well as to diverse viral genes encoded by the Aichi virus, Banna virus, human coronavirus, Dengue virus type 1, Eyach virus, GB virus C, Hantaan virus, hepatitis C, HIV-2, Japanese encephalitis virus, poliovirus, parainfluenza virus, and the Mammalian orthoreovirus 3.
Hsa-mir-206 Vita database	hsa-mir-206 is predicted to target genes of the Human coxsackievirus B2, Crimean-Congo hemorrhagic fever virus, Dengue virus Type 3, GB virus C , Hantaan virus, Hepatitis C, HIV-2, Kadipiro virus, human poliovirus 1 and the Human parainfluenza virus

Glutamate general: One of the ways in which the influenza virus could affect postsynaptic function is via its interactions with the dendritic mRNA transport protein, staufen, to which the NS1 influenza protein binds ³³⁰. Dendrites contain messenger RNA, thought to code for many of the elements necessary for glutamatergic transmission, plasticity and protein synthesis ³³¹ and processes implicated in neuronal plasticity. The herpes virus also triggers the formation of varicosities along the axons of sensory neurones that stain for synaptophysin and closely resemble presynaptic terminals ³³². These effects are mediated by viral activation of the rho GTP binding protein CDC42, which also plays a key role in the maturation of presynaptic glutamatergic terminals ³³³. These varicosities serve as exit sites for the herpes virus, and if they correspond to presynaptic terminals, presumably contain many of the components of these structures (eg synapsins, complexins and syntaxins). The M1 protein of the influenza virus also binds to CDC42 ³³⁴ whose suppression inhibits viral production.

Glutamatergic and related	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
DAO D-amino acid oxidase	NF	NF	NF	NF	NF	NF
DAOA D-amino acid oxidase activator	NF	NF	NF	NF	NF	NF
SRR Serine racemase	NF	NF	NF	NF	NF	NF
NAALAD2 N-acetylated alpha-linked acidic dipeptidase 2	NF	NF	Reduced cerebral N-acetylaspartate/choline ratios have been observed in Herpes simplex encephalitis ^335,336	NF	NF	NF
SLC15A1 solute carrier family 15 (oligopeptide transporter), member 1 (PEPT1)	NF.	NF	NF	NF	NF:Substrates include bacterial derived N-formyl peptides ³³⁷	NF
PRODH Proline dehydrogenase	NF	NF	NF	Expression reduced by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
SLC1A2 solute carrier family 1 (glial high affinity glutamate transporter), member 2	NF	NF	Upregulated by HSV-1 infection of microglia ³³⁸	NF	NF	NF
NOSIAP (CAPON) (also postsynaptic)	NF	NF	NF	NF	NF	NF
CPLX2 Complexin II	NF	NF	NF	NF	NF	NF
SNAP29 synaptosomal-associated protein, 29kDa	NF	NF	NF	NF	NF	NF
SYN2 Synapsin II	NF	NF	NF	NF	NF	NF
SYN3 Synapsin III	NF	NF	NF	NF	NF	NF
STX1A Syntaxin 1a	NF	NF	NF	NF	NF	NF
SYNGR1 Synaptogyrin 1	NF	NF	NF	NF	NF
GRM3 Metabotropic glutamate receptor mgluR3	NF	NF	NF	Expression reduced by rubella infection of human embryo fibroblasts Adamo et al, 2008	NF	NF
GRM4 Metabotropic glutamate receptor mgluR4	NF	NF	NF	NF	NF	NF
GRM8 Metabotropic glutamate receptor mgluR8	NF	NF	NF	NF	NF	NF
GRIA1 AMPA receptor subunit	Neuronal transfection of the influenza nucleoprotein results in the distribution of the viral protein to dendritic spines. The frequency of spontaneous excitatory synaptic activity and the amplitude of miniature excitatory postsynaptic currents is reduced. The results suggest that the viral protein intereed with the expression or anchoring of postsynaptic glutamate receptors ³³⁹	HSV-1 innoculation increases hippocampal excitability but no particular receptor subtype has been examined ³⁴⁰	NF	NF	NF	NF
GRIA4 (AMPA receptor subunit )	See above	NF	NF	NF	NF	NF
GRIK3 Kainate receptor	NF	NF	NF	NF	NF	NF
GRIK4 Kainate receptor	NF	NF	NF	NF	NF	NF
GRID1 glutamate receptor, ionotropic, delta 1	NF	NF	NF	NF	NF	NF
GRIN1 (NMDA receptor subunit NR1)	NF	Hippocampal expression reduced following CMV infection in mice. Also observed in primary neuronal culture ³⁴¹	Expression reduced following the introduction of an attenuated HSV-1 vector to PC12 cells. Correlated with the appearance of viral ICP0 and ICP27 genes ³³⁸ HSV-1 infection increases spinal cord quinolinic acid ³⁴²	NF	Elevated serum and CSF levels of the NMDA agonist quinolinic acid in Lyme disease ³⁴³	NF
GRIN2A NMDA receptor	NF	NF	NMDA receptor antagonism attenuates the effects of HSV-1 encephalitis in mice via an effect on microglial NMDA receptors ³⁴⁴.	NF	NF	NF
GRIN2B NMDA receptor subunit NR2B	In a Rasmussen syndrome patient with seizure onset after influenza A infections, cross-reaction of the patient's lymphocytes with GluR epsilon 2 (GRIN2B) and influenza vaccine components was observed. Database analyses revealed that influenza A virus hemagglutinin and GluR epsilon 2 molecules contain peptides with the patient's HLA class I binding motif (HLA - A*0201)³⁴⁵	NF	See above	NF	NF	NF
GRIN2D NMDA receptor subunit NR2D	NF	NF	See above	NF	NF	NF
GRM5 Metabotropic glutamate receptor mgluR5	NF	NF	NF	NF	NF	NF
APC adenomatous polyposis coli (colorectal tumor suppressor)	NF	NF	Down regulated by HSV-1 infection of rat fibroblasts ⁷⁹	NF	NF	NF
ATXN1 (SCA1): ataxin 1)	NF	NF	NF	Expression reduced by rubella infection of human embryo fibroblasts Adamo et al, 2008	NF	NF
DLG2 Chapsyn-110	Downregulated in neocortex at postnatal days 35/36 following prenatal influemza infection in mice ⁴⁰	NF	NF	NF	NF	NF
DRPLA dentatorubral-pallidoluysian atrophy or atrophin-1	NF	NF	NF	NF	NF	NF
HOMER1	Downregulated in neocortex at postnatal days 35/36 following prenatal influemza infection in mice ⁴⁰	NF	Down regulated by HSV-1 infection of rat fibroblasts ⁷⁹	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
PICK1 protein kinase C alpha binding protein	NF	NF	The herpes virus (HSV-1) uses nectin receptors (PVRL1-3) to gain entry to host cells PICK1 is a scaffolding partner for these receptors ³⁴⁶ and for the Coxsackie virus receptor ³⁴⁷	NF	NF	NF

Miscellaneous	Influenza	Cytomegalovirus	Herpes	Rubella	Borrelia burgdefoori	T. Gondii
ADCYAP1 adenylate cyclase activating polypeptide 1 (pituitary)(PACAP)	NF	NF	Induces Herpes viral activation in HSV-1 infected but quiescent PC12 cells³⁴⁸	NF	NF	NF
ADH1B alcohol dehydrogenase IB (class I), beta polypeptide	NF	NF	NF	NF	NF	NF
ADRA1A adrenergic, alpha-1A-, receptor	NF	NF	NF	NF	NF	NF
AHI1 Abelson helper integration site 1	NF	NF	NF	NF	NF	NF
ALDH3B1 Aldehyde dehydrogenase 3 family, member B1	NF	NF	NF	NF	NF	NF
APOE Apolipoprotein E	NF	NF	Involved in the cerebral uptake of Herpes simplex virus ³⁴⁹	NF	NF	NF
ARHGEF10	NF	NF	NF	NF	NF	NF
BRD1 Bromodomain containing 1	NF	NF	NF	NF	NF	NF
BZRP TSPO translocator protein (18kDa) aka peripheral benzodiazepine receptor	NF	A viral cytomegalovirus mitochondrial Bax inhibitor inhibits cell death induced by PK11195/starvation ³⁵⁰	NF	NF	NF	NF
CCKAR cholecystokinin A receptor	NF	NF	NF	NF	NF	NF
CHGB Chromogranin B	NF	NF	NF	NF	NF	NF
CLOCK circadian locomoter output cycles kaput protein; clock	NF	Experiments using the firefly luciferase gene under the control of the promoter and enhancer of the human cytomegalovirus major immediate-early gene (CMV::luc) in mice show that the viral gene is expressed in vivo around dusk, and during the active locomotor phase of the circadian rhythm ³⁵¹. Similar experiments using culture of the suprachiasmatic nucleus suggest circadian control of viral transgene expression ³⁵².	NF	NF	NF	NF
DDR1 discoidin domain receptor family, member 1(collagen receptor)	NF	NF	NF	NF	Borrelia binds to collagens ³⁵³	NF
DPYSL2 dihydropyrimidinase-like 2	NF: Involved in T-cell migration and polarization. DPYSL2 positive lymphocytes are recuited to the brain by neurotropic viral infection (canine distemper and Rabies virus) ³⁵⁴	NF	NF	NF	NF	NF
DRD2 Dopamine receptor	NF	NF	NF	NF	NF	Neuroleptics inhibit T.gondii replication ³⁵⁵
DRD3 Dopamine receptor	NF	NF	NF	NF	NF	NF
DRD4 Dopamine receptor	NF	NF	NF	NF	NF	NF
DRD5 Dopamine receptor	NF	NF	NF	NF	NF	NF
FXYD6 FXYD domain-containing ion transport regulator 6; phosphohippolin	NF	NF	NF	NF	NF	NF
FZD3 Frizzled 3	NF	NF	NF	NF	NF	NF
GABBR1 GABA-B receptor 1	NF	NF	GABA or TTX inhibit cerebral viral replication ³⁵⁶.	NF	NF	NF
GNAS guanine nucleotide binding protein (G protein), alpha stimulating activity	NF	NF	Expression increased by HSV-1 infection of trigeminal gamglia in mice ³⁰²	NF	NF	NF
GPR78 Orphan GPCR	NF	NF	NF	NF	NF	NF
HMBS Hydroxymethylbilane synthase (Invoved in heme synthesis)	NF	NF	NF	NF	NF	NF
HRH2 H2 Histamine receptor	Plasmacytoid dendritic cells are an important source of interferon type 1 following viral infection. Histamine inhibits interferon release from these cells via the H2 receptor ³⁵⁷	NF	NF	NF	NF	NF
HTR2A Serotonin receptor	NF :The receptor is used by the Polyoma JCV virus for entry into glial cells. The virus causes demyelinating disease ³⁵⁸	NF	Down regulated by HSV-1 infection of rat fibroblasts ⁷⁹	NF	NF	NF
HTR5A Serotonin receptor	NF	NF	NF	NF	NF	NF
HTR6 Serotonin receptor	NF	NF	NF	NF	NF	NF
HTR7 Serotonin receptor	NF	NF	NF	NF	NF	NF
JARID2 jumonji, AT rich interactive domain 2	NF	NF	NF	NF	NF	NF
KCNN3 small conductance calcium-activated potassium channel, (Alias Kca2.3, SK3, SKCA3, hSK3)	NF	NF	NF	NF	NF	NF
KLH1AS (SCA8) spinocerebellar ataxia 8	NF	NF	NF	NF	NF	NF
LGI1 leucine-rich, glioma inactivated 1	NF	NF	NF	NF	NF	NF
MAOA Monoamine oxidase A	NF	NF	NF	NF	NF	NF
MCHR1 (GPR24) Melanocyte concentrating hormone receptor 1	NF	NF	NF	NF	NF	NF
MLC1 (WKL1) megalencephalic leukoencephalopathy with subcortical cysts 1 homolog (human)	NF	NF	NF	NF	NF	NF
MPZL1 Myelin protein zero like 1	NF	NF	NF	NF	NF	NF
ND4 NADH dehydrogenase subunit 4	NF	A viral RNA binds to GRIM-19 which is responsible for the assembly of complex 1 ³⁵⁹	NF	NF	NF	Downregulated by T.Gondii infection of porcine kidney epithelial cells ⁸⁴
NDUFV2 24-kDa subunit of Complex I ; NADH dehydrogenase (ubiquinone) flavoprotein 2 (24kD)	NF	A viral RNA binds to GRIM-19 which is respondible for the assembly of complex 1 ³⁵⁹	NF	NF	NF	NF
NOTCH4 Notch homolog 4	NF	NF	Redo	NF	NF	NF
NPAS3 neuronal PAS domain protein 3	NF	NF	NF	NF	NF	NF
NPY Neuropeptide Y	NF	NF	Upregulated by HSV-1 infection of mouse fibroblasts ³⁶⁰	NF	NF	NF
NTNG1 Netrin G1	NF	NF	NF	NF	NF	NF
NTNG2 Netrin G2	NF	NF	NF	NF	NF	NF
NUMBL numb homolog (Drosophila)-like	NF	NF	NF	NF	NF	NF
OLIG2 oligodendrocyte lineage transcription factor 2	NF	NF	NF	NF	NF	NF
OPRS1 opioid receptor, sigma 1	NF	NF	NF	NF	NF	NF
PAH Phenylalanine hydroxylase	NF	NF	NF	NF	NF	NF
PDE4B Phosphodiesterase 4B	Influenza virus inhibits cAMP phosphodiesterase. Isoform not specified. ³⁶¹	The non-specific phosphodiesterase inhibitor pentoxyfylline promotes the replication of the CMV virus ³⁶²	Phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine and theophylline have growth suppressive effects and reduce cell-to-cell spread of HSV-1 in fibroblasts.³⁶³	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	T. Gondii lacks the ability to synthesise the purine ring and relies on purine salvage from the host ³⁶⁴. Cyclic AMP stimulates T.gondii proliferation in HL-60 cells. CyclicAMP phosphodiesterase inhibitors stimulate and activators inhibit T.Gondii growth ³⁰⁶
PDLIM5 PDZ and LIM domain 5	NF	NF	NF	NF	NF	NF
PER3 period homolog 3	NF	NF	NF	NF	NF	NF
PHOX2B paired-like homeobox 2b	NF	NF	NF	NF	NF	NF
PLXNA2 Plexin A2	NF	NF	NF	Expression reduced by rubella infection of human embryo fibroblasts Adamo et al, 2008	NF	NF
PNOC Prepronociceptin	NF	NF	NF	NF	NF	NF
PPP1R1B	NF	NF	NF		NF	NF
PPP3CC Calcineurin A gamma	NF	NF	NFAT transcription factors play an important role T cell receptor activation and in the immune response. The nuclear imort of NFAT is controlled by calcineurin and NFAT import is blocked by HSV1 infection ³⁶⁵ . In primary neurones calcineurin inhibition increases the expression of the viral ICP0 protein ³⁶⁶	NF	NF	A T.Gondii protein is highly homologous to cyclophilins and calcineurin ³⁶⁷. An FK506- and cyclosporin-binding protein of T.Gondii possesses N-terminal FK506 binding protein P and C-terminal Cyclophilin domains and inhibits calcineurin ³⁶⁸
QK1 Quaking	NF	NF	NF	NF	NF	NF
RBP1				Expression decreased by rubella infection of human embrionic fibroblasts Adamo et al, 2008
RELN Reelin	Reduced cortical and hippocampal immunoreactiviy in influenza-infected mice ³⁶⁹	NF	NF	NF	Borrelia burgdorferi binds to Toll-like receptors and also to the integrin alpha(3)beta(1) (ITGA3), through which it activates the expression of metalloproteases and inflammatory cytokines including TNF and IL1B ³⁷⁰.In the brain, ITGA3 is also known to bind to the extracellular matrix protein Reelin (RELN) ³⁷¹and Reelin/integrin system controls the surface expression of NMDA receptors (GRIN1, GRIN2B) ³⁷²	T.Gondii contact with the cell surface in fibroblasts is mediated by laminins on the parasite surface, which bind to host beta 1 integrins ³⁷³. The Reelin/beta 1 integrin system controls the surface expression of NMDA receptors (GRIN1, GRIN2B) ³⁷², although the effects of T.Gondii on Reelin/NMDA receptor interactions have not been studied.
RGS4 regulator of G-protein signalling 4	Influenza infection increases expression in the amygdala, hypothalamus and cerebellum in mice ³⁷⁴.	NF	NF	Expression increased by rubella infection of human adult fibroblasts Adamo et al, 2008	NF	NF
RHD	NF	NF	NF	NF	NF	NF
RTN4 reticulon 4 (NOGO)	NF	NF	NF	NF	NF	NF
RTN4R Reticulon 4 receptor	NF	NF	NF	NF	NF	NF
S100B	NF	NF	NF	NF	NF	NF
SLC18A1 solute carrier family 18 (vesicular monoamine), member 1	NF	NF	NF	NF	NF	NF
SLC18A2 solute carrier family 18 (vesicular monoamine), member 2	NF	NF	NF	NF	NF	NF
SLC6A3 DAT1 dopamine transporter	NF	NF	NF	NF	NF	Protein downregulated after T.Gondii infection of human fibroblasts ¹¹⁹
SLC6A4 Serotonin transporter	NF	NF	NF	NF	NF	NF
SLIt3	NF	NF	NF	NF	NF	NF
SOX10	NF	NF	NF	NF	NF	NF
SULT4A1 Sulfotransferase 4a1	NF	NF	NF	NF	NF	NF
TAAR6 Trace amine receptor 6	NF	NF	NF	NF	NF	NF
TH Tyrosine hydroxylase	NF	Persistent infection of neuroblastoma cells reduces TH and dopamine beta hydroxylase activity ³⁷⁵	Infection of PC12 cells results in an early decline in TH activity followed by a return to basal levels and a late increase in activity ³⁷⁶	NF	NF	NF
TIMELESS	NF	NF	NF		NF	NF
UCP2 Uncoupling protein 2	NF	NF	NF	NF	NF	UCP2 knockout mice are resistant to T.Gondii infection ³⁷⁷. Generally modifies innate immunity ³⁷⁸
UCP4 (SLC25A27) Uncoupling protein 4	NF	NF	NF	NF	NF	NF
UHMK1	NF	Phosphorylation of p27kip1 by UHMK1 increases its export from the nucleus resulting in increased degradation ³⁷⁹. While no direct interaction between UHMK1 and CMV has been reported, P27kip1 is degraded in cells infected with cytomegalovirus ³⁸⁰.	NF	NF	NF	NF
YWHAH tyrosine 3-monooxygenase/tryptophan 5-monooxygenase-activation protein, eta polypeptide, 14-3-3 eta.	NF	NF	14-3-3 proteins bind to vp16³⁸¹	NF	NF	Protein expression downregulated after T.Gondii infection of fibroblasts ¹¹⁹
ZDHHC8 zinc finger, DHHC domain containing 8	NF	NF	NF	NF	NF	NF

Receptors and growth factors with important neural functions also play an important role in T- and B- lymphocyte function: Some examples are listed below.

Neurotansmitter and growth factor control of T- and B-cells	T-Cells	B-cells
DRD2	Role in T-cell activation. Activates IL10 secretion ³⁸²	Expressed on B-cells ³⁸³
DRD3	Induces homing and T-cell migration ³⁸⁴ : and TNF secretion ³⁸².Expression elevated in schizophrenia³⁸⁵	Expressed on B-cells ³⁸³
DRD4	Induces quiescence inT-Cells ³⁸⁶	-
DRD5	Role in T-cell activation: Induces IL10 and TNF secretion ³⁸²	Expressed on B-cells ³⁸³
SLC6A3	-	Expressed on B-cells ³⁸³
HTR2A	Decrease T cell proliferation ³⁸⁷	-
HTR3	T-cell activation ³⁸⁸	-
HTR7	Enhances T-cell activation ³⁸⁹	-
SLC6A4	Present in T-cells ³⁹⁰	Present in B-cells ³⁹⁰
GRIN1/GRIN2B	Stimulate T-cell activation ³⁹¹	-
GRM5	Impairs T-cell activation ³⁹²	-
BDNF	Released by activated T-cells ³⁹³	Plays a role in B-cell development ³⁹⁴
NTF3	Released by activated T-cells ³⁹³	-

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