1887

Abstract

Human cytomegalovirus (HCMV)-encoded G protein-coupled-receptor US28 is believed to participate in virus dissemination through modulation of cell migration and immune evasion. US28 binds different CC chemokines and the CX3C chemokine CX3CL1. Membrane-anchored CX3CL1 is expressed by immune-activated endothelial cells, causing redirection of CX3CR1-expressing leukocytes in the blood to sites of infection. Here, we used stable transfected cell lines to examine how US28 expression affects cell migration on immobilized full-length CX3CL1, to model how HCMV-infected leukocytes interact with inflamed endothelium. We observed that US28-expressing cells migrated more than CX3CR1-expressing cells when adhering to immobilized CX3CL1. US28-induced migration was G protein-signalling dependent and was blocked by the phospholipase Cβ inhibitor U73122 and the intracellular calcium chelator BAPTA-AM. In addition, migration was inhibited in a dose-dependent manner by competition from CCL2 and CCL5, whereas CCL3 had little effect. Instead of migrating, CX3CR1-expressing cells performed ‘dancing-on-the-spot’ movements, demonstrating that anchored CX3CL1 acts as a strong tether for these cells. At low receptor expression levels, however, no significant difference in migration potential was observed when comparing the migration of CX3CR1- and US28-expressing cells. Thus, these data showed that, in contrast to CX3CR1, which promotes efficient cell capture upon binding to anchored CX3CL1, US28 acts to increase the migration of cells upon binding to the same ligand. Overall, this indicates that infected cells probably move more than uninfected cells in inflamed tissues with high CX3CL1 expression, with soluble chemokines affecting the final migration.

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2013-05-01
2019-12-13
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References

  1. Alcami A. . ( 2003; ). Viral mimicry of cytokines, chemokines and their receptors. . Nat Rev Immunol 3:, 36–50. [CrossRef] [PubMed]
    [Google Scholar]
  2. Atwood B. K. , Lopez J. , Wager-Miller J. , Mackie K. , Straiker A. . ( 2011; ). Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis. . BMC Genomics 12:, 14.[PubMed] [CrossRef]
    [Google Scholar]
  3. Bazan J. F. , Bacon K. B. , Hardiman G. , Wang W. , Soo K. , Rossi D. , Greaves D. R. , Zlotnik A. , Schall T. J. . ( 1997; ). A new class of membrane-bound chemokine with a CX3C motif. . Nature 385:, 640–644. [CrossRef] [PubMed]
    [Google Scholar]
  4. Beisser P. S. , Laurent L. , Virelizier J. L. , Michelson S. . ( 2001; ). Human cytomegalovirus chemokine receptor gene US28 is transcribed in latently infected THP-1 monocytes. . J Virol 75:, 5949–5957. [CrossRef] [PubMed]
    [Google Scholar]
  5. Billstrom M. A. , Lehman L. A. , Scott Worthen G. . ( 1999; ). Depletion of extracellular RANTES during human cytomegalovirus infection of endothelial cells. . Am J Respir Cell Mol Biol 21:, 163–167.[PubMed] [CrossRef]
    [Google Scholar]
  6. Casarosa P. , Bakker R. A. , Verzijl D. , Navis M. , Timmerman H. , Leurs R. , Smit M. J. . ( 2001; ). Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. . J Biol Chem 276:, 1133–1137. [CrossRef] [PubMed]
    [Google Scholar]
  7. Chee M. S. , Satchwell S. C. , Preddie E. , Weston K. M. , Barrell B. G. . ( 1990; ). Human cytomegalovirus encodes three G protein-coupled receptor homologues. . Nature 344:, 774–777. [CrossRef] [PubMed]
    [Google Scholar]
  8. Dankner W. M. , McCutchan J. A. , Richman D. D. , Hirata K. , Spector S. A. . ( 1990; ). Localization of human cytomegalovirus in peripheral blood leukocytes by in situ hybridization. . J Infect Dis 161:, 31–36. [CrossRef] [PubMed]
    [Google Scholar]
  9. Digel M. , Sampaio K. L. , Jahn G. , Sinzger C. . ( 2006; ). Evidence for direct transfer of cytoplasmic material from infected to uninfected cells during cell-associated spread of human cytomegalovirus. . J Clin Virol 37:, 10–20. [CrossRef] [PubMed]
    [Google Scholar]
  10. Fong A. M. , Robinson L. A. , Steeber D. A. , Tedder T. F. , Yoshie O. , Imai T. , Patel D. D. . ( 1998; ). Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. . J Exp Med 188:, 1413–1419. [CrossRef] [PubMed]
    [Google Scholar]
  11. Fong A. M. , Alam S. M. , Imai T. , Haribabu B. , Patel D. D. . ( 2002; ). CX3CR1 tyrosine sulfation enhances fractalkine-induced cell adhesion. . J Biol Chem 277:, 19418–19423. [CrossRef] [PubMed]
    [Google Scholar]
  12. Fraile-Ramos A. , Kledal T. N. , Pelchen-Matthews A. , Bowers K. , Schwartz T. W. , Marsh M. . ( 2001; ). The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. . Mol Biol Cell 12:, 1737–1749.[PubMed] [CrossRef]
    [Google Scholar]
  13. Goda S. , Imai T. , Yoshie O. , Yoneda O. , Inoue H. , Nagano Y. , Okazaki T. , Imai H. , Bloom E. T. . & other authors ( 2000; ). CX3C-chemokine, fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and -independent mechanisms. . J Immunol 164:, 4313–4320.[PubMed] [CrossRef]
    [Google Scholar]
  14. Green S. R. , Han K. H. , Chen Y. , Almazan F. , Charo I. F. , Miller Y. I. , Quehenberger O. . ( 2006; ). The CC chemokine MCP-1 stimulates surface expression of CX3CR1 and enhances the adhesion of monocytes to fractalkine/CX3CL1 via p38 MAPK. . J Immunol 176:, 7412–7420.[PubMed] [CrossRef]
    [Google Scholar]
  15. Haskell C. A. , Cleary M. D. , Charo I. F. . ( 1999; ). Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. . J Biol Chem 274:, 10053–10058. [CrossRef] [PubMed]
    [Google Scholar]
  16. Haskell C. A. , Cleary M. D. , Charo I. F. . ( 2000; ). Unique role of the chemokine domain of fractalkine in cell capture. Kinetics of receptor dissociation correlate with cell adhesion. . J Biol Chem 275:, 34183–34189. [CrossRef] [PubMed]
    [Google Scholar]
  17. Hjortø G. M. , Hansen M. , Larsen N. B. , Kledal T. N. . ( 2009; ). Generating substrate bound functional chemokine gradients in vitro. . Biomaterials 30:, 5305–5311. [CrossRef] [PubMed]
    [Google Scholar]
  18. Imai T. , Hieshima K. , Haskell C. , Baba M. , Nagira M. , Nishimura M. , Kakizaki M. , Takagi S. , Nomiyama H. . & other authors ( 1997; ). Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. . Cell 91:, 521–530. [CrossRef] [PubMed]
    [Google Scholar]
  19. Kerfoot S. M. , Lord S. E. , Bell R. B. , Gill V. , Robbins S. M. , Kubes P. . ( 2003; ). Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment. . Eur J Immunol 33:, 729–739. [CrossRef] [PubMed]
    [Google Scholar]
  20. Kledal T. N. , Rosenkilde M. M. , Schwartz T. W. . ( 1998; ). Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. . FEBS Lett 441:, 209–214. [CrossRef] [PubMed]
    [Google Scholar]
  21. Landolfo S. , Gariglio M. , Gribaudo G. , Lembo D. . ( 2003; ). The human cytomegalovirus. . Pharmacol Ther 98:, 269–297. [CrossRef] [PubMed]
    [Google Scholar]
  22. Margulies B. J. , Browne H. , Gibson W. . ( 1996; ). Identification of the human cytomegalovirus G protein-coupled receptor homologue encoded by UL33 in infected cells and enveloped virus particles. . Virology 225:, 111–125. [CrossRef] [PubMed]
    [Google Scholar]
  23. Patel D. D. , Koopmann W. , Imai T. , Whichard L. P. , Yoshie O. , Krangel M. S. . ( 2001; ). Chemokines have diverse abilities to form solid phase gradients. . Clin Immunol 99:, 43–52. [CrossRef] [PubMed]
    [Google Scholar]
  24. Pleskoff O. , Tréboute C. , Alizon M. . ( 1998; ). The cytomegalovirus-encoded chemokine receptor US28 can enhance cell–cell fusion mediated by different viral proteins. . J Virol 72:, 6389–6397.[PubMed]
    [Google Scholar]
  25. Randolph-Habecker J. R. , Rahill B. , Torok-Storb B. , Vieira J. , Kolattukudy P. E. , Rovin B. H. , Sedmak D. D. . ( 2002; ). The expression of the cytomegalovirus chemokine receptor homolog US28 sequesters biologically active CC chemokines and alters IL-8 production. . Cytokine 19:, 37–46. [CrossRef] [PubMed]
    [Google Scholar]
  26. Shulby S. A. , Dolloff N. G. , Stearns M. E. , Meucci O. , Fatatis A. . ( 2004; ). CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration, and survival of human prostate cancer cells. . Cancer Res 64:, 4693–4698. [CrossRef] [PubMed]
    [Google Scholar]
  27. Smith M. S. , Bentz G. L. , Alexander J. S. , Yurochko A. D. . ( 2004; ). Human cytomegalovirus induces monocyte differentiation and migration as a strategy for dissemination and persistence. . J Virol 78:, 4444–4453. [CrossRef] [PubMed]
    [Google Scholar]
  28. Streblow D. N. , Soderberg-Naucler C. , Vieira J. , Smith P. , Wakabayashi E. , Ruchti F. , Mattison K. , Altschuler Y. , Nelson J. A. . ( 1999; ). The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. . Cell 99:, 511–520. [CrossRef] [PubMed]
    [Google Scholar]
  29. Stropes M. P. , Schneider O. D. , Zagorski W. A. , Miller J. L. , Miller W. E. . ( 2009; ). The carboxy-terminal tail of human cytomegalovirus (HCMV) US28 regulates both chemokine-independent and chemokine-dependent signaling in HCMV-infected cells. . J Virol 83:, 10016–10027. [CrossRef] [PubMed]
    [Google Scholar]
  30. Tarrant T. K. , Patel D. D. . ( 2006; ). Chemokines and leukocyte trafficking in rheumatoid arthritis. . Pathophysiology 13:, 1–14. [CrossRef] [PubMed]
    [Google Scholar]
  31. Tsou C. L. , Haskell C. A. , Charo I. F. . ( 2001; ). Tumor necrosis factor-α-converting enzyme mediates the inducible cleavage of fractalkine. . J Biol Chem 276:, 44622–44626. [CrossRef] [PubMed]
    [Google Scholar]
  32. Umehara H. , Goda S. , Imai T. , Nagano Y. , Minami Y. , Tanaka Y. , Okazaki T. , Bloom E. T. , Domae N. . ( 2001; ). Fractalkine, a CX3C-chemokine, functions predominantly as an adhesion molecule in monocytic cell line THP-1. . Immunol Cell Biol 79:, 298–302. [CrossRef] [PubMed]
    [Google Scholar]
  33. van der Strate B. W. , Hillebrands J. L. , Lycklama à Nijeholt S. S. , Beljaars L. , Bruggeman C. A. , Van Luyn M. J. , Rozing J. , The T. H. , Meijer D. K. . & other authors ( 2003; ). Dissemination of rat cytomegalovirus through infected granulocytes and monocytes in vitro and in vivo. . J Virol 77:, 11274–11278. [CrossRef] [PubMed]
    [Google Scholar]
  34. Vischer H. F. , Hulshof J. W. , de Esch I. J. , Smit M. J. , Leurs R. . ( 2007; ). Virus-encoded G-protein-coupled receptors: constitutively active (dys)regulators of cell function and their potential as drug target. . Ernst Schering Found Symp Proc 2006:, 187–210. [CrossRef] [PubMed]
    [Google Scholar]
  35. Volin M. V. , Huynh N. , Klosowska K. , Chong K. K. , Woods J. M. . ( 2007; ). Fractalkine is a novel chemoattractant for rheumatoid arthritis fibroblast-like synoviocyte signaling through MAP kinases and Akt. . Arthritis Rheum 56:, 2512–2522. [CrossRef] [PubMed]
    [Google Scholar]
  36. Vomaske J. , Melnychuk R. M. , Smith P. P. , Powell J. , Hall L. , DeFilippis V. , Früh K. , Smit M. , Schlaepfer D. D. . & other authors ( 2009; ). Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility. . PLoS Pathog 5:, e1000304. [CrossRef] [PubMed]
    [Google Scholar]
  37. Waldhoer M. , Casarosa P. , Rosenkilde M. M. , Smit M. J. , Leurs R. , Whistler J. L. , Schwartz T. W. . ( 2003; ). The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. . J Biol Chem 278:, 19473–19482. [CrossRef] [PubMed]
    [Google Scholar]
  38. Zhuravskaya T. , Maciejewski J. P. , Netski D. M. , Bruening E. , Mackintosh F. R. , St Jeor S. . ( 1997; ). Spread of human cytomegalovirus (HCMV) after infection of human hematopoietic progenitor cells: model of HCMV latency. . Blood 90:, 2482–2491.[PubMed]
    [Google Scholar]
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