Epistemic_Statements  

CORD-19:7d787fd0d2ef92f3430670b2c19a5102e67fd167 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-96 Epistemic_statement denotes The CD200-CD200R1 Inhibitory Signaling Pathway: Immune Regulation and Host-Pathogen Interactions
T2 107-268 Epistemic_statement 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.
T3 666-934 Epistemic_statement 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.
T4 935-1202 Epistemic_statement 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.
T5 1498-1843 Epistemic_statement 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.
T6 2221-2383 Epistemic_statement denotes The mechanisms by which inhibitory receptors limit the amplitude of proinflammatory responses have been described in detail (Long, 1999; Ravetch & Lanier, 2000) .
T7 3408-3785 Epistemic_statement 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.
T8 3793-3927 Epistemic_statement denotes Pathogens can express proteins that efficiently bind to a variety of inhibitory receptors that normally distinguish self from nonself.
T9 4541-4753 Epistemic_statement 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) .
T10 4754-4854 Epistemic_statement denotes This suggests that virus and host together have evolved to modulate signaling through this receptor.
T11 5340-5488 Epistemic_statement 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) .
T12 5489-5614 Epistemic_statement denotes UL18 can bind to both CD94/NKG2 and leukocyte inhibitory receptor (LIR)-1 and it is thought that m144 may interact similarly.
T13 6128-6299 Epistemic_statement 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.
T14 7424-7591 Epistemic_statement 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.
T15 7592-7937 Epistemic_statement 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.
T16 8163-8480 Epistemic_statement 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) .
T17 8481-8705 Epistemic_statement 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) .
T18 8706-8956 Epistemic_statement 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) .
T19 9264-9386 Epistemic_statement denotes These data suggest that many pathogens can take advantage of host inhibitory receptors to modulate inflammatory responses.
T20 9387-9581 Epistemic_statement 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 .
T21 9960-10185 Epistemic_statement 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.
T22 10186-10252 Epistemic_statement denotes Each of these mechanisms can ultimately be exploited by pathogens.
T23 11230-11465 Epistemic_statement 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 ).
T24 11898-12080 Epistemic_statement 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.
T25 12766-13000 Epistemic_statement 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) .
T26 13778-14008 Epistemic_statement 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) .
T27 14265-14412 Epistemic_statement denotes These data show that in the case of Toxoplasmosis, increased inflammatory responses, likely through TLR signaling, are detrimental to the pathogen.
T28 14780-14859 Epistemic_statement denotes Virulence of L. amazonensis can be restored by treatment with soluble CD200-Fc.
T29 15004-15131 Epistemic_statement denotes However, CD200-Fc treatment in L. major-infected WT mice shifts its virulence to that of L. amazonensis (Cortez et al., 2011) .
T30 15406-15478 Epistemic_statement denotes Interestingly, L. amazonensis increased CD200 expression on macrophages.
T31 15479-15600 Epistemic_statement denotes Macrophages have generally been found to express CD200R1, which can then interact with nonmyeloid cells expressing CD200.
T32 15601-15755 Epistemic_statement denotes These findings suggest that, at least in the case of L. amazonensis, macrophages can inhibit neighboring macrophages by expressing both CD200R1 and CD200.
T33 15756-15982 Epistemic_statement 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) .
T34 15983-16081 Epistemic_statement denotes It may be that these exosomes contain CD200, which can then bind to CD200R1 on nearby macrophages.
T35 16082-16178 Epistemic_statement denotes Whether or how this would occur is not clear, though it is certainly an interesting possibility.
T36 16179-16278 Epistemic_statement denotes Alternatively, macrophages expressing CD200 may interact with activated T-cells expressing CD200R1.
T37 16770-16932 Epistemic_statement 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) .
T38 16933-17114 Epistemic_statement 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.
T39 17493-17702 Epistemic_statement 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.
T40 17703-17878 Epistemic_statement denotes This suggests that chronic infections lead to increased expression of CD200 and CD200R1 and subsequently a decrease in antipathogenic mediators, allowing pathogen persistence.
T41 17879-17930 Epistemic_statement denotes How pathogens regulate CD200 expression is unclear.
T42 17931-18044 Epistemic_statement denotes However, studies have shown that expression of CD200 is regulated by transcription factors and enhancer elements.
T43 18716-18842 Epistemic_statement denotes Perhaps pathogens utilize these enhancer sites and transcription factors to induce CD200 expression following TLR recognition.
T44 18981-19179 Epistemic_statement 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) .
T45 20365-20506 Epistemic_statement denotes These findings indicate that coronavirus infections require a functional CD200: CD200R1 signaling interaction to limit type I IFN production.
T46 21302-21498 Epistemic_statement 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) .
T47 21832-22060 Epistemic_statement 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.
T48 22179-22321 Epistemic_statement denotes Interestingly, CD200R1 KO mice exhibit decreased viral pathogenesis and pathology in response to influenza infection (Goulding et al., 2011) .
T49 22322-22412 Epistemic_statement denotes These results seem counter-intuitive compared to the previous findings with CD200 KO mice.
T50 22413-22618 Epistemic_statement 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.
T51 23298-23529 Epistemic_statement 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.
T52 23530-23675 Epistemic_statement denotes Treatment also mildly reduced lesions in chronically infected mice, though this would need to be combined with another drug to prove efficacious.
T53 23676-23960 Epistemic_statement 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.
T54 24327-24448 Epistemic_statement denotes Therefore, we predicted that CD200R1 KO mice would show increased morbidity and mortality in response to HSV-1 infection.
T55 24449-24604 Epistemic_statement 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.
T56 24605-24789 Epistemic_statement 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) .
T57 24790-24968 Epistemic_statement 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.
T58 24969-25162 Epistemic_statement 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.
T59 25736-26009 Epistemic_statement 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) .
T60 26192-26399 Epistemic_statement 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) .
T61 27448-27588 Epistemic_statement denotes Interestingly, this inhibition was not seen when basophils were stimulated with IL-3, suggesting specificity for CD200 inhibitory functions.
T62 28039-28272 Epistemic_statement 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) .
T63 29052-29135 Epistemic_statement denotes This is thought to occur through interactions with CD200R1 but has not been proven.
T64 29136-29233 Epistemic_statement denotes Other viruses express CD200 orthologs, but its direct role in mediating viral fitness is unclear.
T65 29295-29532 Epistemic_statement 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) .
T66 29533-29741 Epistemic_statement 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.
T67 29742-30029 Epistemic_statement 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.
T68 30030-30180 Epistemic_statement denotes Understanding how these infectious agents use the CD200: CD200R1 axis to downregulate host defenses can potentially be exploited in clinical settings.
T69 30181-30395 Epistemic_statement 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.
T70 30589-30694 Epistemic_statement denotes This drug could also be used to treat pathogenic infections that are impacted by CD200:CD200R1 signaling.
T71 30695-30967 Epistemic_statement 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.
T72 30968-31168 Epistemic_statement 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.
T73 31169-31521 Epistemic_statement 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.
T74 31642-31813 Epistemic_statement 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.
T75 31979-32231 Epistemic_statement 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.
T76 32232-32493 Epistemic_statement 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.
T77 32494-32605 Epistemic_statement denotes There are still many questions about how CD200R1 regulates inflammatory responses in myeloid cells and T-cells.
T78 32606-32761 Epistemic_statement 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.
T79 32965-33088 Epistemic_statement denotes The concept that inhibitory receptors can be multifunctional and may be required for proinflammatory signaling has emerged.
T80 33089-33326 Epistemic_statement 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) .
T81 33592-33760 Epistemic_statement 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.
T82 34423-34763 Epistemic_statement 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.