1887

Abstract

Endothelial cells (ECs) are a site of human cytomegalovirus (HCMV) productive replication, haematogenous dissemination and persistence, and are assumed to play a critical role in the development of HCMV-associated vascular diseases. Although early reports have shown the presence of HCMV antigens and DNA in lymphoid tissues, the ability of HCMV to infect lymphatic ECs (LECs) has remained unaddressed due to the lack of a suitable system. This study provided evidence that a clinical isolate of HCMV (retaining its natural endotheliotropism) was able to productively infect purified lymph node-derived LECs and that it dysregulated the expression of several LEC genes involved in the inflammatory response to viral infection. Qualitative and quantitative analysis of virus-free supernatants from HCMV-infected LEC cultures revealed virus-induced secretion of several cytokines, chemokines and growth factors, many of which are involved in the regulation of EC physiological properties. Indeed, functional assays demonstrated that the secretome produced by HCMV-infected LECs stimulated angiogenesis in both LECs and blood ECs, and that neutralization of either interleukin (IL)-6 or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the secretome caused the loss of its angiogenic properties. The involvement of IL-6 and GM-CSF in the HCMV-mediated angiogenesis was further supported by the finding that the recombinant cytokines reproduced the angiogenic effects of the HCMV secretome. These findings suggest that HCMV induces haemangiogenesis and lymphangiogenesis through an indirect mechanism that relies on the stimulation of IL-6 and GM-CSF secretion from infected cells.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.025395-0
2011-03-01
2019-10-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/3/650.html?itemId=/content/journal/jgv/10.1099/vir.0.025395-0&mimeType=html&fmt=ahah

References

  1. Adler, B. & Sinzger, C. ( 2009; ). Endothelial cells in HCMV infection: one host cell out of many or a crucial target for virus spread? Thromb Haemost 102, 1057–1063.
    [Google Scholar]
  2. Almeida, G. D., Porada, C. D., St Jeor, S. & Ascensao, J. L. ( 1994; ). Human cytomegalovirus alters interleukin-6 production by endothelial cells. Blood 83, 370–376.
    [Google Scholar]
  3. Almeida-Porada, G., Porada, C. D., Shanley, J. D. & Ascensao, J. L. ( 1997; ). Altered production of GM-CSF and IL-8 in cytomegalovirus-infected, IL-1-primed umbilical cord endothelial cells. Exp Hematol 25, 1278–1285.
    [Google Scholar]
  4. Bentz, G. L. & Yurochko, A. D. ( 2008; ). Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and β1 and β3 integrins. Proc Natl Acad Sci U S A 105, 5531–5536.[CrossRef]
    [Google Scholar]
  5. Boriskin, Y. S., Moore, P., Murday, A. J., Booth, J. C. & Butcher, P. D. ( 1999; ). Human cytomegalovirus genome sequences in lymph nodes. Microbes Infect 1, 279–283.[CrossRef]
    [Google Scholar]
  6. Botto, S., Streblow, D.N., DeFilippis, V., White, L., Kreklywich, G.N., Smith, P.P. & Caposio, P. ( 2010; ). Il-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of surviving. Blood 117, 352–361.
    [Google Scholar]
  7. Britt, W. ( 2008; ). Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol 325, 417–470.
    [Google Scholar]
  8. Caposio, P., Riera, L., Hahn, G., Landolfo, S. & Gribaudo, G. ( 2004; ). Evidence that the human cytomegalovirus 46-kDa UL72 protein is not an active dUTPase but a late protein dispensable for replication in fibroblasts. Virology 325, 264–276.[CrossRef]
    [Google Scholar]
  9. Caposio, P., Musso, T., Luganini, A., Inoue, H., Gariglio, M., Landolfo, S. & Gribaudo, G. ( 2007a; ). Targeting the NF-κB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells. Antiviral Res 73, 175–184.[CrossRef]
    [Google Scholar]
  10. Caposio, P., Luganini, A., Hahn, G., Landolfo, S. & Gribaudo, G. ( 2007b; ). Activation of the virus-induced IKK/NF-κB signalling axis is critical for the replication of human cytomegalovirus in quiescent cells. Cell Microbiol 9, 2040–2054.[CrossRef]
    [Google Scholar]
  11. Carmeliet, P. ( 2003; ). Angiogenesis in health and disease. Nat Med 9, 653–660.[CrossRef]
    [Google Scholar]
  12. Caruso, A., Caselli, E., Fiorentini, S., Rotola, A., Prandini, A., Garrafa, E., Saba, E., Alessandri, G., Cassai, E. & Di Luca, D. ( 2009; ). U94 of human herpesvirus 6 inhibits in vitro angiogensis and lymphoangiogenesis. Proc Natl Acad Sci U S A 106, 20446–20451.[CrossRef]
    [Google Scholar]
  13. Chen, T. & Hudnall, S. D. ( 2006; ). Anatomical mapping of human herpesvirus reservoirs of infection. Mod Pathol 19, 726–737.[CrossRef]
    [Google Scholar]
  14. Cueni, L. N. & Detmar, M. ( 2008; ). The lymphatic system in health and disease. Lymphat Res Biol 6, 109–122.[CrossRef]
    [Google Scholar]
  15. Digel, M. & Sinzger, C. ( 2006; ). Determinant of endothelial cell tropism of human cytomegalovirus. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 445–464. Edited by Reddehase, M.. Norfolk. : Caister Academic Press.
    [Google Scholar]
  16. Dumortier, J., Streblow, D. N., Moses, A. V., Jacobs, J. M., Kreklywich, C. N., Camp, D., Smith, R. D., Orloff, S. L. & Nelson, J. A. ( 2008; ). Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J Virol 82, 6524–6535.[CrossRef]
    [Google Scholar]
  17. Garrafa, E., Trainini, L., Benetti, A., Saba, E., Fezzardi, L., Lorusso, B., Borghetti, P., Bottio, T., Ceri, E. & other authors ( 2005; ). Isolation, purification, and heterogeneity of human lymphatic endothelial cells from different tissues. Lymphology 38, 159–166.
    [Google Scholar]
  18. Garrafa, E., Alessandri, G., Benetti, A., Turetta, D., Corradi, A., Cantoni, A. M., Cervi, E., Bonardelli, S., Parati, E. & other authors ( 2006; ). Isolation and characterization of lymphatic microvascular endothelial cells from human tonsils. J Cell Physiol 207, 107–113.[CrossRef]
    [Google Scholar]
  19. Hoshina, T., Kusuhara, K., Saito, M., Hara, T., Matsuura, S., Yano, T., Aoki, T. & Hara, T. ( 2009; ). Cytomegalovirus-associated protein-losing enteropathy resulting from lymphangiectasia in an immunocompetent child. Jpn J Infect Dis 62, 236–238.
    [Google Scholar]
  20. Jarvis, M. A. & Nelson, J. A. ( 2007; ). Human cytomegalovirus tropism for endothelial cells: not all endothelial cells are created equal. J Virol 81, 2095–2101.[CrossRef]
    [Google Scholar]
  21. Ji, R. C. ( 2005; ). Characteristics of lymphatic endothelial cells in physiological and pathological conditions. Histol Histopathol 20, 155–175.
    [Google Scholar]
  22. Kapetanos, D., Abuouda, H., Iodanidis, F., Katsinelos, P. & Kitis, G. ( 2010; ). Unique case of intestinal lymphangiectasia in an immunocompetent adult, caused by CMV and EBV co-infection. Ann Gastroenterol 23, 136–138.
    [Google Scholar]
  23. Karlsen, T. V., Karkkainen, M. J., Alitalo, K. & Wiig, H. ( 2006; ). Transcapillary fluid balance consequences of missing initial lymphatics studied in a mouse model of primary lymphoedema. J Physiol 574, 583–596.[CrossRef]
    [Google Scholar]
  24. Krubasik, D., Eisenach, P. A., Kunz-Schughart, L. A., Murphy, G. & English, W. R. ( 2008; ). Granulocyte-macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane-type 1 matrix metalloproteinase expression in vitro. Int J Cancer 122, 1261–1272.
    [Google Scholar]
  25. Luo, M. H. & Fortunato, E. A. ( 2007; ). Long-term infection and shedding of human cytomegalovirus in T98G glioblastoma cells. J Virol 81, 10424–10436.[CrossRef]
    [Google Scholar]
  26. Mocarski, E. S., Jr, Shenk, T. & Pass, R. F. ( 2006; ). Cytomegaloviruses. In Fields Virology, 5th edn, pp. 2701–2772. Edited by Knipe, D. M. & Howley, P. M.. Philadelphia. : Lippincott Williams & Wilkins.
    [Google Scholar]
  27. Nakase, H., Itani, T., Mimura, J., Takeuchi, R., Kawasaki, T., Komori, H., Hashimoto, K. & Chiba, T. ( 1998; ). Transient protein-losing enteropathy associated with cytomegalovirus in a noncompromised host: a case report. Am J Gastroenterol 93, 1005–1006.[CrossRef]
    [Google Scholar]
  28. Podgrabinska, S., Braun, P., Velasco, P., Kloos, B., Pepper, M. S. & Skobe, M. ( 2002; ). Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A 99, 16069–16074.[CrossRef]
    [Google Scholar]
  29. Reinhardt, B., Schaarschmidt, P., Bossert, A., Luske, A., Finkenzeller, G., Mertens, T. & Michel, D. ( 2005; ). Upregulation of functionally active vascular endothelial growth factor by human cytomegalovirus. J Gen Virol 86, 23–30.[CrossRef]
    [Google Scholar]
  30. Revello, M. G. & Gerna, G. ( 2010; ). Human cytomegalovirus tropism for endothelial/epithelial cells: scientific background and clinical implications. Rev Med Virol 20, 136–155.[CrossRef]
    [Google Scholar]
  31. Revello, M. G., Baldanti, F., Percivalle, E., Sarasini, A., De-Giuli, L., Genini, E., Lilleri, D., Labò, N. & Gerna, G. ( 2001; ). In vitro selection of human cytomegalovirus variants unable to transfer virus and virus products from infected cells to polymorphonuclear leukocytes and to grow in endothelial cells. J Gen Virol 82, 1429–1438.
    [Google Scholar]
  32. Ricotta, D., Alessandri, G., Pollara, C., Fiorentini, S., Favilli, F., Tosetti, M., Mantovani, A., Grassi, M., Garrafa, E. & other authors ( 2001; ). Adult human heart microvascular endothelial cells are permissive for non-lytic infection by human cytomegalovirus. Cardiovasc Res 49, 440–448.[CrossRef]
    [Google Scholar]
  33. Sinzger, C., Digel, M. & Jahn, G. ( 2008; ). Cytomegalovirus cell tropism. Curr Top Microbiol Immunol 325, 63–83.
    [Google Scholar]
  34. Söderberg-Nauclér, C. ( 2006; ). Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer? J Intern Med 259, 219–246.[CrossRef]
    [Google Scholar]
  35. Söderberg-Nauclér, C. ( 2008; ). HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 41, 218–223.[CrossRef]
    [Google Scholar]
  36. Streblow, D. N., Durmontier, J., Moses, A. V., Orloff, S. L. & Nelson, J. A. ( 2008; ). Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Curr Top Microbiol Immunol 325, 397–415.
    [Google Scholar]
  37. Wuest, T. R. & Carr, D. J. J. ( 2010; ). VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 207, 101–115.[CrossRef]
    [Google Scholar]
  38. Yao, J. S., Zhai, W., Young, W. L. & Yang, G. Y. ( 2006; ). Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9. Biochem Biophys Res Commun 342, 1396–1404.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.025395-0
Loading
/content/journal/jgv/10.1099/vir.0.025395-0
Loading

Data & Media loading...

Supplements

vol. , part 3, pp. 650 - 660

HCMV VR1814 infection rates in LECs infected at an m.o.i. of 3 [PDF](72 KB)



PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error