CORD-19-Sentences  

CORD-19:7d787fd0d2ef92f3430670b2c19a5102e67fd167 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-47 Sentence denotes The CD200-CD200R1 Inhibitory Signaling Pathway:
TextSentencer_T2 48-96 Sentence denotes Immune Regulation and Host-Pathogen Interactions
TextSentencer_T3 98-106 Sentence denotes Abstract
TextSentencer_T4 107-268 Sentence denotes The CD200:CD200R1 inhibitory signaling pathway has been implicated in playing a prominent role in limiting inflammation in a wide range of inflammatory diseases.
TextSentencer_T5 269-454 Sentence denotes CD200R1 signaling inhibits the expression of proinflammatory molecules including tumor necrosis factor, interferons, and inducible nitric oxide synthase in response to selected stimuli.
TextSentencer_T6 455-665 Sentence denotes Unsurprisingly, due to the regulatory role that CD200R1 plays in multiple inflammatory pathways, an increasing number of parasitic, bacterial, and viral pathogens exploit this pathway to suppress host defenses.
TextSentencer_T7 666-934 Sentence denotes A complete understanding of the pathways regulated by CD200R1 signaling and the diverse mechanisms that pathogens have evolved to manipulate the CD200:CD200R1 pathway can help identify clinical situations where targeting this interaction can be of therapeutic benefit.
TextSentencer_T8 935-1202 Sentence denotes In this review, we compare CD200R1 to other pathogen-targeted inhibitory receptors and highlight how this signaling pathway is utilized by a diverse number of pathogens and, therefore, may represent a novel targeting strategy for the treatment of infectious diseases.
TextSentencer_T9 1203-1204 Sentence denotes 1
TextSentencer_T10 1206-1327 Sentence denotes Hosts and pathogens have evolved mechanisms to defeat each other in the battle for control over the host's immune system.
TextSentencer_T11 1328-1497 Sentence denotes A successful infection requires that the pathogen positively regulate its survival, replication, and spread while suppressing the pathogen-specific host immune response.
TextSentencer_T12 1498-1843 Sentence denotes Conversely, it is essential that the host immune response be appropriately controlled to respond to and remove pathogens while avoiding excessive production of cytokines, chemical mediators such as reactive oxygen species (ROS), and the release of proteolytic enzymes all of which can lead to increased tissue damage and morbidity and mortality.
TextSentencer_T13 1844-2093 Sentence denotes Immune cells express receptors, such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors, which recognize and respond to pathogens with the induction of antivirulence genes and generation of chemical mediators.
TextSentencer_T14 2094-2220 Sentence denotes At the same time these cells express inhibitory receptors that limit the amplitude of the response to prevent immunopathology.
TextSentencer_T15 2221-2383 Sentence denotes The mechanisms by which inhibitory receptors limit the amplitude of proinflammatory responses have been described in detail (Long, 1999; Ravetch & Lanier, 2000) .
TextSentencer_T16 2384-2517 Sentence denotes For the purpose of this review, we will focus on members of the inhibitory receptor superfamily that have been targeted by pathogens.
TextSentencer_T17 2518-2775 Sentence denotes Based on the structure of the extracellular domains, there are two major classes within the inhibitory receptor superfamily: the immunoglobulin (Ig) superfamily and the calcium-dependent carbohydrate-binding (C-type) lectin family (Long, 1999) (Fig. 5.1A ).
TextSentencer_T18 2776-2962 Sentence denotes Most members of the inhibitory receptor superfamily have an immunoreceptor tyrosinebased inhibitory motif (ITIM) in the cytoplasmic tail of the protein (Vely & Vivier, 1997) (Fig. 5.1 ).
TextSentencer_T19 2963-3247 Sentence denotes Upon activation of the receptor, phosphorylation of tyrosine residues in the ITIM recruits adaptor proteins such as src homology 2-containing protein tyrosine phosphatases (SHPs) and SH2 domain-containing inositol phosphatase-1 (SHIP-1) (Daeron, Jaeger, Du Pasquier, & Vivier, 2008) .
TextSentencer_T20 3248-3407 Sentence denotes This ultimately leads to a decrease in immune functions including cytokine production, calcium release, migration, and proliferation (Ravetch & Lanier, 2000) .
TextSentencer_T21 3408-3792 Sentence denotes Many inhibitory receptors also have paired activating receptors, which contain cytoplasmic immunoreceptor tyrosine-based activation motifs and associate with adaptor proteins like DNAX-activating protein of 12 kDa (DAP12) or the FcRγ chain through a positively charged residue in the transmembrane region (McVicar et al., 1998) to induce proinflammatory signaling events ( Fig. 5.1 ).
TextSentencer_T22 3793-3927 Sentence denotes Pathogens can express proteins that efficiently bind to a variety of inhibitory receptors that normally distinguish self from nonself.
TextSentencer_T23 3928-4000 Sentence denotes In this way, they avoid recognition and promote persistence in the host.
TextSentencer_T24 4001-4118 Sentence denotes Herpesviruses and poxvi-ruses are exceptionally skilled at avoiding or subverting host immune responses (Table 5 .1).
TextSentencer_T25 4119-4371 Sentence denotes Murine cytomegalovirus (MCMV) expresses m157, which is structurally similar to MHC class I proteins and binds to the inhibitory receptor Ly49I in MCMV-susceptible mouse strains to prevent NK-mediated killing (Arase & Lanier, 2004; Arase et al., 2002) .
TextSentencer_T26 4372-4540 Sentence denotes The mouse Ly49 family of molecules is expressed on NK cells that recognize the α1 and α2 subunits of H-2D MHC class I molecules (Karlhofer, Ribaudo, & Yokoyama, 1992) .
TextSentencer_T27 4541-4753 Sentence denotes Interestingly, MCMV-resistant mouse strains, but not MCMV-susceptible strains, express the activating receptor Ly49H, which also binds to m157 but initiates NK killing of the infected cells (Smith et al., 2002) .
TextSentencer_T28 4754-4854 Sentence denotes This suggests that virus and host together have evolved to modulate signaling through this receptor.
TextSentencer_T29 4855-5051 Sentence denotes In fact, when MCMV is continuously passaged in Ly49H positive cells in culture, the virus will quickly generate mutations in m157 to avoid binding to the activating receptor (Voigt et al., 2003) .
TextSentencer_T30 5052-5188 Sentence denotes Human cytomegalovirus (HCMV) expresses the protein UL18, a homolog of MHC class I antigens (Cosman et al., 1997; Reyburn et al., 1997) .
TextSentencer_T31 5189-5339 Sentence denotes MCMV also expresses m144, which also functions as a MHC class I mimic and is required for efficient viral replication in vivo (Farrell et al., 1997) .
TextSentencer_T32 5340-5488 Sentence denotes Both UL18 and m144 form the three α domains typical of MHC class I molecules and both can bind to β2M (Farrell et al., 1997; Reyburn et al., 1997) .
TextSentencer_T33 5489-5614 Sentence denotes UL18 can bind to both CD94/NKG2 and leukocyte inhibitory receptor (LIR)-1 and it is thought that m144 may interact similarly.
TextSentencer_T34 5615-5949 Sentence denotes The CD94/NKG2 receptors recognize the nonclassical MHC class I molecules human HLA-E and mouse Qa1 (Brooks et al., 1999; Houchins, Lanier, Niemi, Phillips, & Ryan, 1997; Lee et al., 1998; Vance, Kraft, Altman, Jensen, & Raulet, 1998) , which are expressed on all cell types except red blood cells (Kuroki, Furukawa, & Maenaka, 2012) .
TextSentencer_T35 5950-6127 Sentence denotes Human LIR-1 recognizes epitopes shared by most MHC class I molecules through interactions with the α3 and β2M domains (Chapman et al., 1999; Willcox, Thomas, & Bjorkman, 2003) .
TextSentencer_T36 6128-6299 Sentence denotes In fact, LIR-1 binds to UL18 more tightly than host class I molecules (Chapman et al., 1999) , indicating that this receptor may have evolved specifically to bind to UL18.
TextSentencer_T37 6300-6425 Sentence denotes Furthermore, the leader sequence of the HCMV protein UL40 is identical to the MHC class I, HLA-E associated peptide HLA-Cw03.
TextSentencer_T38 6426-6576 Sentence denotes CD94/NKG2A will recognize HCMV-infected cells as self based on presentation of the HLA-E-like peptide and will not kill them (Ulbrecht et al., 2000) .
TextSentencer_T39 6577-6804 Sentence denotes The rat cytomegalovirus (RCMV) C-type lectin-like gene (rctl) is characterized as an early gene whose structure closely resembles the mouse and rat C-type lectin related protein Clr-b (Voigt et al., 2001 (Voigt et al., , 2007 .
TextSentencer_T40 6805-6997 Sentence denotes The inhibitory receptor NKR-P1B, expressed mainly on NK cells (Voigt et al., 2007) , recognizes Clr-b as a ligand, which is expressed on almost all hematopoietic cells (Carlyle et al., 2004) .
TextSentencer_T41 6998-7160 Sentence denotes Following infection with RCMV, there is a rapid upregulation of RCTL, which counteracts downregulation of Clr-b expression by host cells in response to infection.
TextSentencer_T42 7161-7284 Sentence denotes Through a non-MHC class I recognition mechanism, RCTL inhibits NK cell-mediated lysis by directly interacting with NKR-P1B.
TextSentencer_T43 7285-7423 Sentence denotes Furthermore, RCTL-deficient virus exhibits decreased virulence and is more easily cleared from the host by NK cells (Voigt et al., 2007) .
TextSentencer_T44 7424-7591 Sentence denotes Interestingly, the activation receptor NKR-P1A also recognizes RCTL, indicating that host defenses have evolved to counteract the ability of RCTL to evade recognition.
TextSentencer_T45 7592-7937 Sentence denotes A variety of poxviruses encode a CD47 mimic (Arase & Lanier, 2004; Cameron, Barrett, Mann, Lucas, & McFadden, 2005) , and based on evidence from other paired inhibitory/ activation receptors, as described earlier, it has been suggested that these mimics may interact with signal-regulatory protein (SIRP)α to downregulate myeloid cell functions.
TextSentencer_T46 7938-8162 Sentence denotes SIRPα, expressed mainly on myeloid cells and neurons (Adams et al., 1998; Alblas et al., 2005) , binds to CD47 to regulate leukocyte chemotaxis and proinflammatory cytokine production (Cameron, Barrett, Mann, et al., 2005) .
TextSentencer_T47 8163-8480 Sentence denotes The myxoma virus CD47 mimic, M128L, is required for lethal infections in rabbits and appears to regulate macrophage activation and recruitment, as M128L-deficient virus-infected rabbits exhibit increased inducible nitric oxide synthase (iNOS)-positive cells at infection sites (Cameron, Barrett, Mann, et al., 2005) .
TextSentencer_T48 8481-8705 Sentence denotes The activating receptor, SIRPβ does not bind to CD47, and its ligand is unknown, but may have evolved to counteract pathogen infections and/or recognize pathogen-infected cells (Arase & Lanier, 2004; Barclay & Brown, 2006) .
TextSentencer_T49 8706-8956 Sentence denotes In addition to viral decoys, several bacterial strains, including S. aureus and E. coli, can bind to the mouse paired Ig-like receptors (PIRs) PIR-B and PIR-A1 and human LIR-1 to suppress macrophage proinflammatory responses (Nakayama et al., 2007) .
TextSentencer_T50 8957-9263 Sentence denotes The murine PIRs, which are structurally similar to the human LIRs, recognize MHC class I molecules (Nakamura, Kobayashi, & Takai, 2004) and are expressed on a variety of cell types, including macrophages, dendritic cells, mast cells, and B cells (Kubagawa, Burrows, & Cooper, 1997; Kubagawa et al., 1999) .
TextSentencer_T51 9264-9386 Sentence denotes These data suggest that many pathogens can take advantage of host inhibitory receptors to modulate inflammatory responses.
TextSentencer_T52 9387-9581 Sentence denotes CD200R1 is an Ig superfamily transmembrane glycoprotein expressed on the surface of myeloid cells; it can also be induced in certain T-cell subsets (Caserta et al., 2012; Wright et al., , 2003 .
TextSentencer_T53 9582-9712 Sentence denotes CD200R1 interacts with CD200, which is also an Ig superfamily transmembrane glycoprotein, to down regulate myeloid cell functions.
TextSentencer_T54 9713-9959 Sentence denotes CD200 is expressed on the surface of a variety of cells including neurons, epithelial cells, endothelial cells, fibroblasts, lymphoid cells, and astrocytes (Caserta et al., 2012; Costello et al., 2011; Hoek et al., 2000; Snelgrove et al., 2008) .
TextSentencer_T55 9960-10185 Sentence denotes The regulation of CD200R1 signaling can occur by posttranslational modification-namely, phosphorylation of tyrosines in the CD200R1 cytoplasmic tail-or by the inducible expression or downregulation of either CD200R1 or CD200.
TextSentencer_T56 10186-10252 Sentence denotes Each of these mechanisms can ultimately be exploited by pathogens.
TextSentencer_T57 10253-10340 Sentence denotes Unlike most immune inhibitory receptors, CD200R1 does not contain an ITIM ( Fig. 5.1 ).
TextSentencer_T58 10341-10576 Sentence denotes Instead, human CD200R1 contains three cytoplasmic tyro-sine residues, Y291, Y294, and Y302 (Y286, Y289, and Y297 in the mouse), one of which, Y302/Y297, is located within a phosphotyrosine binding (PTB) domain recognition motif (NPxY).
TextSentencer_T59 10577-10866 Sentence denotes Stimulation by CD200 leads to the phosphorylation of these tyrosines by Src kinases, which recruit the adapter protein downstream of tyrosine kinase (Dok) 2 through its PTB domain (Mihrshahi, Barclay, & Brown, 2009; Mihrshahi & Brown, 2010; Zhang, Cherwinski, Sedgwick, & Phillips, 2004) .
TextSentencer_T60 10867-11035 Sentence denotes Y302/Y297 and to a lesser extent Y291/Y286 are the major tyrosine residues required for CD200R1 association with Dok2 (Mihrshahi et al., 2009; Zhang & Phillips, 2006) .
TextSentencer_T61 11036-11229 Sentence denotes Dok2 serves as the major initiator of signaling through CD200R1, beginning with binding to Ras-GTPase activating protein (RasGAP) and is required for CD200R1 function (Mihrshahi et al., 2009) .
TextSentencer_T62 11230-11465 Sentence denotes This is in contrast to ITIM containing inhibitory receptors, which utilize SHPs and SHIP-1 as the major initiator proteins and Dok proteins as secondary modulators of downstream signaling (Daeron et al., 2008; Mihrshahi et al., 2009 ).
TextSentencer_T63 11466-11661 Sentence denotes Pathogens have found ways to exploit the CD200:CD200R1 signaling pathway by altering expression of either CD200 or CD200R1, or by expressing a CD200 mimic to engage the host CD200R1 (Table 5 .2).
TextSentencer_T64 11662-11791 Sentence denotes In certain situations, the greatest threat to the host is the excessive inflammation seen in response to the infectious organism.
TextSentencer_T65 11792-11897 Sentence denotes In these cases, the disruption of the CD200:CD200R1 axis in model systems leads to the death of the host.
TextSentencer_T66 11898-12080 Sentence denotes In the cases of intracellular parasites, this can be deleterious to the pathogen as well, as these organisms benefit from the survival of the host for long-term growth and expansion.
TextSentencer_T67 12081-12247 Sentence denotes In other cases, the subset of antipathogen genes that are suppressed by the engagement of CD200R1 directly allows survival of the pathogen at the expense of the host.
TextSentencer_T68 12248-12447 Sentence denotes Antipathogen molecules, such as ROS that include nitric oxide (NO), superoxide, and hydroxyl radicals, preformed mediators, and interferons (IFNs) are a subset of proinflammatory genes and mediators.
TextSentencer_T69 12448-12765 Sentence denotes As a protective measure against tissue damage, host macrophages adaptively modify chromatin to allow them to become unresponsive to repetitive or persistent signaling by TLRs (e.g., TLR4 and lipopolysaccharide (LPS) tolerance) (Foster, Hargreaves, & Medzhitov, 2007) , leading to decreased pro-inflammatory signaling.
TextSentencer_T70 12766-13000 Sentence denotes Certain antipathogen molecules, however, are not dampened after prolonged TLR signaling because chromatin modification allows antipathogen genes to remain responsive to TLR4 in the presence of ongoing infection (Foster et al., 2007) .
TextSentencer_T71 13001-13104 Sentence denotes Pathogens also employ various strategies to engage downregulatory mechanisms to suppress host defenses.
TextSentencer_T72 13105-13248 Sentence denotes These are illustrated by the mechanisms various pathogens use to manipulate the CD200:CD200R1 axis or to manipulate other inhibitory receptors.
TextSentencer_T73 13249-13268 Sentence denotes 2.2.1.1 Toxoplasma:
TextSentencer_T74 13269-13443 Sentence denotes In WT mice, Toxoplasma gondii induces increased surface expression of CD200R1 and CD200 in microglia and blood vessel endothelial cells, respectively (Deckert et al., 2006) .
TextSentencer_T75 13444-13649 Sentence denotes In CD200 KO mice, microglial cells exhibited increased proliferation, activation, and higher expression of MHC II, tumor necrosis factor (TNFα), and iNOS during infection in chronic T. gondii encephalitis.
TextSentencer_T76 13650-13777 Sentence denotes CD200 KO mice also exhibited decreased parasite burden and decreased mortality compared to WT mice following chronic infection.
TextSentencer_T77 13778-14008 Sentence denotes This is likely due to the fact that CD200 KO mice exhibit an increased inflammatory phenotype in response to the TLR ligands, including significantly higher IL-6 and TNFα release and IκBα phosphor-ylation (Costello et al., 2011) .
TextSentencer_T78 14009-14147 Sentence denotes It is known that T. gondii stimulation of mouse TLR11 induces IL-12, which is key for the survival of the host (Yarovinsky et al., 2005) .
TextSentencer_T79 14148-14264 Sentence denotes TLRs 2 and 4 have also been implicated in the inflammatory response to T. gondii (Debierre-Grockiego et al., 2007) .
TextSentencer_T80 14265-14412 Sentence denotes These data show that in the case of Toxoplasmosis, increased inflammatory responses, likely through TLR signaling, are detrimental to the pathogen.
TextSentencer_T81 14413-14595 Sentence denotes Leishmania amazonensis, which causes severe disease in both humans and mice, induces CD200 mRNA and protein expression in bone marrow macrophages from WT mice (Cortez et al., 2011) .
TextSentencer_T82 14596-14779 Sentence denotes Upregulation of CD200 was essential for replication and development of systemic Leishmaniasis as L. amazonensis replication and virulence are significantly decreased in CD200 KO mice.
TextSentencer_T83 14780-14859 Sentence denotes Virulence of L. amazonensis can be restored by treatment with soluble CD200-Fc.
TextSentencer_T84 14860-15003 Sentence denotes Not all species of Leishmania have evolved this mechanism, as L. major, which causes cutaneous but not systemic disease, does not induce CD200.
TextSentencer_T85 15004-15131 Sentence denotes However, CD200-Fc treatment in L. major-infected WT mice shifts its virulence to that of L. amazonensis (Cortez et al., 2011) .
TextSentencer_T86 15132-15275 Sentence denotes L. amazonensis has evolved to utilize CD200 expression as a mechanism for inhibiting both NO production and induction of iNOS during infection.
TextSentencer_T87 15276-15405 Sentence denotes This was confirmed by treatment of macrophages with an iNOS inhibitor, which, in turn, lead to increased replication of L. major.
TextSentencer_T88 15406-15478 Sentence denotes Interestingly, L. amazonensis increased CD200 expression on macrophages.
TextSentencer_T89 15479-15600 Sentence denotes Macrophages have generally been found to express CD200R1, which can then interact with nonmyeloid cells expressing CD200.
TextSentencer_T90 15601-15755 Sentence denotes These findings suggest that, at least in the case of L. amazonensis, macrophages can inhibit neighboring macrophages by expressing both CD200R1 and CD200.
TextSentencer_T91 15756-15982 Sentence denotes Macrophages infected with intracellular pathogens can release exosomes, small vesicles containing various membrane proteins, which can provide signals to naiïve macrophages (Bhatnagar, Shinagawa, Castellino, & Schorey, 2007) .
TextSentencer_T92 15983-16081 Sentence denotes It may be that these exosomes contain CD200, which can then bind to CD200R1 on nearby macrophages.
TextSentencer_T93 16082-16178 Sentence denotes Whether or how this would occur is not clear, though it is certainly an interesting possibility.
TextSentencer_T94 16179-16278 Sentence denotes Alternatively, macrophages expressing CD200 may interact with activated T-cells expressing CD200R1.
TextSentencer_T95 16279-16368 Sentence denotes CD200 KO mice are more susceptible to infection with Neisseria meningitidis than WT mice.
TextSentencer_T96 16369-16655 Sentence denotes While there was no significant difference in bacteremia between WT and CD200 KO mice, CD200 KO mice had higher systemic levels of IL-6 and TNFα, higher numbers of F4/80+CD11b+macrophages, and expressed higher levels of MHC class II molecules on macrophages (Mukhopadhyay et al., 2010) .
TextSentencer_T97 16656-16769 Sentence denotes Furthermore, CD200 expression is upregulated in bone marrow macrophages following infection with N. meningitidis.
TextSentencer_T98 16770-16932 Sentence denotes This is likely due to recognition of Neisserial LPS by TLR4, since TLR ligation can increase CD200 surface expression in macrophages (Mukhopadhyay et al., 2010) .
TextSentencer_T99 16933-17114 Sentence denotes These data suggest that in WT mice, CD200:CD200R1 signaling plays a role in regulating the response to N. meningitidis, but does not necessarily affect the survival of the pathogen.
TextSentencer_T100 17115-17240 Sentence denotes Therefore, increased mortality in this model is mediated by uncontrolled inflammation, not uncontrolled pathogen replication.
TextSentencer_T101 17241-17401 Sentence denotes Both CD200 and CD200R1 are upregulated and coexpressed in chronically activated CD4 T-cells from mice infected with Schistosoma mansoni and Salmonella enterica.
TextSentencer_T102 17402-17492 Sentence denotes These cells also lost the ability to generate TNFα and exhibited increased IL-4 secretion.
TextSentencer_T103 17493-17702 Sentence denotes Furthermore, in patients chronically infected with Schistosoma haematobium, there was a correlation between CD200R1 expression and parasite load and almost all IL-4 secreting CD4 T-cells were CD200R1 positive.
TextSentencer_T104 17703-17878 Sentence denotes This suggests that chronic infections lead to increased expression of CD200 and CD200R1 and subsequently a decrease in antipathogenic mediators, allowing pathogen persistence.
TextSentencer_T105 17879-17930 Sentence denotes How pathogens regulate CD200 expression is unclear.
TextSentencer_T106 17931-18044 Sentence denotes However, studies have shown that expression of CD200 is regulated by transcription factors and enhancer elements.
TextSentencer_T107 18045-18194 Sentence denotes Constitutive CD200 expression is regulated by the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) (Chen, Marsden, & Gorczynski, 2006 .
TextSentencer_T108 18195-18450 Sentence denotes Furthermore, there are three enhancer sites (cis-elements) upstream of the CD200 transcriptional start site, a NF-κB binding site, an IFNγ-activation site (GAS), and an IFN-stimulatory response element-2, that are important for inducible CD200 expression.
TextSentencer_T109 18451-18559 Sentence denotes NF-κB, STAT1, and IFN regulator factor-1 bind to these enhancer elements, respectively (Chen et al., 2009 ).
TextSentencer_T110 18560-18715 Sentence denotes Furthermore, it was determined that the NF-κB transcription factor, c-Rel, was required for TLR-induced upregulation of CD200 (Mukhopadhyay et al., 2010) .
TextSentencer_T111 18716-18842 Sentence denotes Perhaps pathogens utilize these enhancer sites and transcription factors to induce CD200 expression following TLR recognition.
TextSentencer_T112 18843-18980 Sentence denotes CD200 is also a target of p53 and is upregulated on apoptotic cells to decrease responsiveness to self-antigen (Rosenblum et al., 2004) .
TextSentencer_T113 18981-19179 Sentence denotes The mechanisms that pathogens employ to induce the expression of CD200R1 are also unclear, although their interaction with TLRs is one mechanism (Dentesano et al., 2012; Mukhopadhyay et al., 2010) .
TextSentencer_T114 19180-19298 Sentence denotes It has recently been discovered that inducible expression of CD200R1 is regulated by C/EBPβ (Dentesano et al., 2012) .
TextSentencer_T115 19299-19432 Sentence denotes Microglial cells exhibit a significant decrease in CD200R1 mRNA and protein expression following stimulation with LPS, a TLR4 ligand.
TextSentencer_T116 19433-19478 Sentence denotes This decrease is not seen in C/EBPβ KO cells.
TextSentencer_T117 19479-19587 Sentence denotes Additionally, overexpression of C/EBPβ led to a significant decrease in CD200R1 mRNA and protein expression.
TextSentencer_T118 19588-19676 Sentence denotes C/EBPβ directly binds to the CD200R1 promoter to inhibit expression in LPStreated cells.
TextSentencer_T119 19677-19787 Sentence denotes Furthermore, it was found that histone deacetylase 1 interacts with C/EBPβ to downregulate CD200R1 expression.
TextSentencer_T120 19788-19993 Sentence denotes Loss of CD200R1 signaling, through use of CD200 KO mice, results in an increase in inflammatory signaling, specifically type I IFN in response to TLR7 ligands, including mouse hepatitis corona virus (MHV).
TextSentencer_T121 19994-20112 Sentence denotes MHV serves as an infection model for the severe acute respiratory syndrome coronavirus (De Albuquerque et al., 2006) .
TextSentencer_T122 20113-20286 Sentence denotes Lack of inflammatory signaling control had a positive effect on MHV clearance as CD200 KO mice exhibited decreased viral replication and viral titers (Karnam et al., 2012) .
TextSentencer_T123 20287-20364 Sentence denotes Infected CD200 KO mice also had increased levels of IFNα compared to WT mice.
TextSentencer_T124 20365-20506 Sentence denotes These findings indicate that coronavirus infections require a functional CD200: CD200R1 signaling interaction to limit type I IFN production.
TextSentencer_T125 20507-20667 Sentence denotes The opposite is true for influenza A where CD200 KO mice were highly susceptible to the effects of uncontrolled inflammation in response to pulmonary infection.
TextSentencer_T126 20668-20875 Sentence denotes These mice demonstrated more weight loss and increased mortality in response to influenza than WT mice (Karnam et al., 2012; Snelgrove et al., 2008) , even though viral clearance was similar in both strains.
TextSentencer_T127 20876-21045 Sentence denotes CD200 KO mice also had higher levels of NO in lung homogenates, as well as increased levels of IL-6, TNFα, IFNγ, and macrophage inflammatory protein 1α in lavage fluids.
TextSentencer_T128 21046-21301 Sentence denotes Furthermore, the administration of CD200-Fc or anti-CD200R1 agonist was able to partially reverse the phenotype of CD200 KO mice, leading to less weight loss and lower cellularity than untreated CD200 KO mice following infection (Snelgrove et al., 2008) .
TextSentencer_T129 21302-21498 Sentence denotes In WT mice, alveolar macrophages exhibit increased expression of CD200R1, which would serve to limit inflammatory responses to the virus, and thus, limit immunopathology (Snelgrove et al., 2008) .
TextSentencer_T130 21499-21644 Sentence denotes In this case, the role of the CD200:CD200R1 axis is to protect the host from cytokine storm, which is the major cause of morbidity and mortality.
TextSentencer_T131 21645-21831 Sentence denotes Influenza-infected CD200R1 KO mice show less bacterial load and exhibit decreased pathogenesis and mortality than WT mice following S. pneumoniae superinfection (Goulding et al., 2011) .
TextSentencer_T132 21832-22060 Sentence denotes This is thought to occur because during the resolution phase of an influenza infection, apoptotic monocytes/macrophages in the lung express CD200 on their surface while alveolar macrophages upregulate CD200R1 surface expression.
TextSentencer_T133 22061-22178 Sentence denotes This leads to decreased alveolar macrophage responsiveness and increased susceptibility to bacterial superinfections.
TextSentencer_T134 22179-22321 Sentence denotes Interestingly, CD200R1 KO mice exhibit decreased viral pathogenesis and pathology in response to influenza infection (Goulding et al., 2011) .
TextSentencer_T135 22322-22412 Sentence denotes These results seem counter-intuitive compared to the previous findings with CD200 KO mice.
TextSentencer_T136 22413-22618 Sentence denotes However, the authors suggest that this may be due to the limited expression of the receptor, compared to the broad expression of the ligand, but further studies need to be performed in order to prove this.
TextSentencer_T137 22619-22763 Sentence denotes Nonetheless, the increased inflammatory response seen in CD200R1 KO mice provides protection to the host in terms of a bacterial superinfection.
TextSentencer_T138 22764-22992 Sentence denotes Herpes simplex virus (HSV)-1 mediated keratitis (stromal keratitis) is a chronic infection that causes an influx of CD200R1-expressing cells into the cornea, leading to inflammatory lesions and blindness (Sarangi et al., 2009) .
TextSentencer_T139 22993-23136 Sentence denotes A variety of cell types, including myeloid cells, upregulate CD200R1 on their surface following ocular HSV-1 infection (Sarangi et al., 2009 ).
TextSentencer_T140 23137-23297 Sentence denotes CD200-Fc treatment of ocular HSV-1 infected mice caused decreased CD11b+ immune cells in the cornea, decreased inflammatory lesions, and decreased angiogenesis.
TextSentencer_T141 23298-23529 Sentence denotes These mice also had decreased cellularity in the spleen and draining lymph nodes and this was associated with a decrease in IFNγ-producing T-cells and an increase in FoxP3+ T-regulatory cells both in lymphoid tissue and the cornea.
TextSentencer_T142 23530-23675 Sentence denotes Treatment also mildly reduced lesions in chronically infected mice, though this would need to be combined with another drug to prove efficacious.
TextSentencer_T143 23676-23960 Sentence denotes These results indicate that CD200:CD200R1 signaling plays a key role in modulating inflammation during a viral infection and provides further evidence that decreasing the inflammatory milieu following a viral infection can actually have a beneficial role for unwanted immunopathology.
TextSentencer_T144 23961-24088 Sentence denotes We have recently examined the role of the CD200:CD200R1 axis in the mouse model of HSV-1 encephalitis (Soberman et al., 2012) .
TextSentencer_T145 24089-24326 Sentence denotes A significant component of the morbidity and mortality in this model is the release of cytokines and chemokines triggered by the interaction of HSV-1 with macrophages and resident microglial cells through TLR2 (Kurt-Jones et al., 2004) .
TextSentencer_T146 24327-24448 Sentence denotes Therefore, we predicted that CD200R1 KO mice would show increased morbidity and mortality in response to HSV-1 infection.
TextSentencer_T147 24449-24604 Sentence denotes However, CD200R1 KO mice were markedly protected against infection and exhibited a decrease in viral titers and HSV-1 glycoprotein expression in the brain.
TextSentencer_T148 24605-24789 Sentence denotes Furthermore, the levels of IFNβ were decreased in both the serum and brain, suggesting that the main driving force in survival was decreased viral replication (Soberman et al., 2012) .
TextSentencer_T149 24790-24968 Sentence denotes Whether decreased viral titers are due to increased antipathogenic defenses in CD200R1 KO mice or due to a direct effect of CD200R1 on viral replication remains to be determined.
TextSentencer_T150 24969-25162 Sentence denotes When we examined the interaction of HSV-1 with thioglycollate-induced peritoneal macrophages we uncovered a potentially far more complex relationship between CD200R1 and cell signaling by TLR2.
TextSentencer_T151 25163-25275 Sentence denotes Rather than show an amplified generation of IL-6 in response to HSV-1, the cytokine response was blunted by 80%.
TextSentencer_T152 25276-25328 Sentence denotes This was not seen in response to LPS, a TLR4 ligand.
TextSentencer_T153 25329-25459 Sentence denotes Furthermore, the surface expression of TLR2 following HSV-1 infection of macrophages was not upregulated (Soberman et al., 2012) .
TextSentencer_T154 25460-25595 Sentence denotes have directly utilized the downregulatory signaling pathways mediated by CD200:CD200R1 interactions for their survival within the host.
TextSentencer_T155 25596-25735 Sentence denotes Members of the herpesviruses and poxviruses have incorporated or evolved orthologs of the host CD200 protein in their genome (Table 5 .3).
TextSentencer_T156 25736-26009 Sentence denotes Perhaps the best characterized is the Kaposi's sarcoma-associated herpes-virus or human herpesvirus 8 or (HHV8) K14 gene, which encodes a viral ortholog of CD200 (vOX2) that is expressed on the surface of infected cells during the lytic phase (Foster-Cuevas et al., 2004) .
TextSentencer_T157 26010-26191 Sentence denotes Although vOX2 shares 36-40% identity with human CD200, both vOX2 and CD200 bind to CD200R1 with equivalent affinity and avidity (Foster-Cuevas et al., 2004; Misstear et al., 2012) .
TextSentencer_T158 26192-26399 Sentence denotes In vitro, vOX2 can downregulate TNFα, granulocyte colony-stimulating factor (G-CSF), and monocyte chemoattractant protein-1 release from macrophages activated with IFNγ and LPS (Foster-Cuevas et al., 2004) .
TextSentencer_T159 26400-26673 Sentence denotes When comparing the function of CD200 and vOX2, Misstear et al. (2012) found that APCs (cell lines that express native HLA-A2 and HLA-B8) transduced to express either CD200 or vOX2 suppressed T-cell IFNγ secretion, ERK1/2 and AKT phosphorylation, and mobilization of CD107a.
TextSentencer_T160 26674-26892 Sentence denotes CD200 and vOX2 also contributes to maintenance of the homeostasis of antigen-specific T-cell responses in vivo by negatively regulating their activity in a manner similar to CTLA-4 and PDL-1/2 (Misstear et al., 2012) .
TextSentencer_T161 26893-27055 Sentence denotes Human herpesviruses 6 and 7 also express CD200 orthologs that bind to human CD200R1 (Shiratori et al., 2005) , though their function is not as well characterized.
TextSentencer_T162 27056-27151 Sentence denotes Human CD200 and HHV8 vOX2 have also been found to function in downregulating basophil function.
TextSentencer_T163 27152-27447 Sentence denotes Basophils have the highest basal expression level of CD200R1 in human peripheral blood, and activation through FcεR1 engagement, measured by CD11b upregulation and histamine release, was blocked by cross-linking CD200R1 with either human CD200 or vOX2 soluble proteins (Shiratori et al., 2005) .
TextSentencer_T164 27448-27588 Sentence denotes Interestingly, this inhibition was not seen when basophils were stimulated with IL-3, suggesting specificity for CD200 inhibitory functions.
TextSentencer_T165 27589-27653 Sentence denotes Rhesus rhadinovirus (RRV) is a gammaherpesvirus similar to HHV8.
TextSentencer_T166 27654-27806 Sentence denotes RRV expresses a viral CD200 protein, R15, that is expressed on the surface of infected cells and released into the supernatant (Langlais et al., 2006) .
TextSentencer_T167 27807-27977 Sentence denotes Similar to other viral CD200 orthologs, R15 decreases TNFα mRNA and cytokine release from PMA-activated THP-1 macrophages as well as primary rhesus monocytes/macrophages.
TextSentencer_T168 27978-28038 Sentence denotes These inhibition levels were similar to that of human CD200.
TextSentencer_T169 28039-28272 Sentence denotes The myxoma virus CD200 ortholog, M141, can function as a global inhibitor of macrophage and lymphocyte activation, leading to increased pathology and viral spread (Cameron, Barrett, Liu, Lucas, & McFadden, 2005; Zhang et al., 2009) .
TextSentencer_T170 28273-28434 Sentence denotes M141 is expressed on the virion of myxoma viruses and contains a single Ig-like domain, similar to the N-terminal region of cellular CD200 (Zhang et al., 2009) .
TextSentencer_T171 28435-28629 Sentence denotes M141-deficient virus-infected rabbits exhibited significantly decreased pathology, including decreased lesion size and number as well as increased healing (Cameron, Barrett, Liu, et al., 2005) .
TextSentencer_T172 28630-28804 Sentence denotes There was also a significant increase in the number of iNOS+cells recruited to sites of infection and activated T-cells in lymph nodes (Cameron, Barrett, Liu, et al., 2005) .
TextSentencer_T173 28805-29051 Sentence denotes Additionally, mouse macrophages infected with M141-deficient virus exhibited an activated phenotype, including increased TNFα and G-CSF levels, whereas WT virus-infected macrophages did not, due to decreased NF-κB signaling (Zhang et al., 2009) .
TextSentencer_T174 29052-29135 Sentence denotes This is thought to occur through interactions with CD200R1 but has not been proven.
TextSentencer_T175 29136-29233 Sentence denotes Other viruses express CD200 orthologs, but its direct role in mediating viral fitness is unclear.
TextSentencer_T176 29234-29294 Sentence denotes Such is the case for the e127 CD200-like protein of rat CMV.
TextSentencer_T177 29295-29532 Sentence denotes With approximately 56% identity to the host CD200 protein, e127 binds to CD200R1 with equivalent affinity, however, it does not significantly affect viral replication or myeloid activity in vitro or in vivo (Foster-Cuevas et al., 2011) .
TextSentencer_T178 29533-29741 Sentence denotes This suggests that although CD200 mimics provide an evolutionary advantage to a variety of pathogens, its role may not be entirely the same in each infection and its effect upon binding to CD200R1 may differ.
TextSentencer_T179 29742-30029 Sentence denotes It is clear, based on the number of pathogens that have evolved to exploit CD200 and CD200R1 expression as well as the widespread expression of CD200 mimics in viral genomes, that the CD200:CD200R1 signaling pathway plays a major role in host:pathogen interactions and pathogen survival.
TextSentencer_T180 30030-30180 Sentence denotes Understanding how these infectious agents use the CD200: CD200R1 axis to downregulate host defenses can potentially be exploited in clinical settings.
TextSentencer_T181 30181-30395 Sentence denotes Furthermore, it is important to completely uncover how CD200R1 regulates immune responses, both dependent and independent of CD200 ligation, as this may provide important insight in the development of therapeutics.
TextSentencer_T182 30396-30588 Sentence denotes An antibody that targets CD200 to block CD200R1 signaling (Kretz-Rommel et al., 2008) is currently in clinical testing for the treatment of cancer (ClinicalTrials.gov identifier: NCT00648739).
TextSentencer_T183 30589-30694 Sentence denotes This drug could also be used to treat pathogenic infections that are impacted by CD200:CD200R1 signaling.
TextSentencer_T184 30695-30967 Sentence denotes In addition to utilizing currently available therapeutics for the treatment of viral infections, it is an intriguing possibility to target viral CD200 orthologs to stimulate viral clearance, as opposed to blocking all signaling through targeting the host CD200 or CD200R1.
TextSentencer_T185 30968-31168 Sentence denotes This virus-specific targeting strategy would allow normal host immune response regulation to continue, avoiding potential immunopathology, while blocking the ability of a virus to replicate unchecked.
TextSentencer_T186 31169-31521 Sentence denotes Though the CD200:CD200R1 axis has been implicated to play a role in transplant tolerance (Gorczynski, 2001; Yu, Chen, & Gorczynski, 2013) , one can speculate that disrupting this relationship in posttransplant patients, or other immunosuppressed patients may actually have short-term benefit under conditions where viral infections can become an issue.
TextSentencer_T187 31522-31641 Sentence denotes Viral infections in renal transplant recipients, for example, remain a significant problem (Weikert & Blumberg, 2008) .
TextSentencer_T188 31642-31813 Sentence denotes In situations where they become difficult to control with antiviral therapy, the major option is to decrease immunosuppressive therapy and restore host antiviral defenses.
TextSentencer_T189 31814-31978 Sentence denotes Viruses most commonly associated with transplant tolerance include CMV, HSV-1, HHV8, Epstein-Barr, Varicella Zoster, BK, and PC viruses (Weikert & Blumberg, 2008) .
TextSentencer_T190 31979-32231 Sentence denotes Though pretransplant screening combined with prophy-lactic treatment with antiviral therapy has been very effective in limiting morbidity caused by these infectious agents, there are times when this is not sufficient, especially with BK and PC viruses.
TextSentencer_T191 32232-32493 Sentence denotes Since some of these viruses target the CD200:CD200R1 signaling pathway, and likely more, blocking the interaction of CD200 with CD200R1 using an antibody or small molecule approach could support more efficient viral clearance while preserving immunosuppression.
TextSentencer_T192 32494-32605 Sentence denotes There are still many questions about how CD200R1 regulates inflammatory responses in myeloid cells and T-cells.
TextSentencer_T193 32606-32761 Sentence denotes Only a few studies have looked at the signaling molecules within cells that associate with the cytoplasmic domain of CD200R1 following ligation with CD200.
TextSentencer_T194 32762-32964 Sentence denotes Furthermore, our recent findings that CD200R1 plays an immunomodulatory role in TLR2 surface expression and signaling add another level of complexity to an already multifunctional signaling interaction.
TextSentencer_T195 32965-33088 Sentence denotes The concept that inhibitory receptors can be multifunctional and may be required for proinflammatory signaling has emerged.
TextSentencer_T196 33089-33326 Sentence denotes For example, the T-and B-cell coreceptor CD150 contains a motif in its cytoplasmic tail, called the immunoreceptor tyrosine-based switch motif (ITSM), that can recruit either inhibitory or activating molecules (Shlapatska et al., 2001) .
TextSentencer_T197 33327-33591 Sentence denotes Additionally, the NK cell receptor 2B4 can induce either inhibitory or activating signals depending on the level of expression, amount of receptor cross-linking, and availability of adaptor molecules (Chlewicki, Velikovsky, Balakrishnan, Mariuzza, & Kumar, 2008) .
TextSentencer_T198 33592-33760 Sentence denotes Although CD200R1 has neither an ITIM nor an ITSM domain, it is possible that an alternative domain in the cytoplasmic tail can modulate anti-or proinflammatory signals.
TextSentencer_T199 33761-33909 Sentence denotes This is the case for the inhibitory receptors CTLA-4, Tim-3, Lag-3, and CD160, none of which contain ITIM or ITSM motifs (Odorizzi & Wherry, 2012) .
TextSentencer_T200 33910-34028 Sentence denotes Classes and cytoplasmic signaling domains of the inhibitory receptor superfamily. (A) Classes of inhibitory receptors.
TextSentencer_T201 34029-34213 Sentence denotes Inhibitory receptors are separated into two major classes based on their extracellular domains: the immunoglobulin (Ig) superfamily and the carbohydrate-binding (C-type) lectin family.
TextSentencer_T202 34214-34422 Sentence denotes Many members of these inhibitory receptor families have affiliated activating receptors, which contain a charged residue in the transmembrane region, denoted by a plus sign. (B) Cytoplasmic inhibitory motifs.
TextSentencer_T203 34423-34763 Sentence denotes Most inhibitory receptors contain an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic region to recruit adaptor proteins upon activation, however the CD200R1 cytoplasmic region contains three tyrosine residues (locations listed as mouse/human), which play a role in adaptor protein interactions upon phosphorylation.
TextSentencer_T204 34764-34862 Sentence denotes LIR, leukocyte inhibitory receptor; PIR, paired Ig-like receptor; SIRP, signal-regulatory protein.