Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jan;71(1):42–49. doi: 10.1128/jvi.71.1.42-49.1997

CD9, a tetraspan transmembrane protein, renders cells susceptible to canine distemper virus.

S Löffler 1, F Lottspeich 1, F Lanza 1, D O Azorsa 1, V ter Meulen 1, J Schneider-Schaulies 1
PMCID: PMC191022  PMID: 8985321

Abstract

Canine distemper virus (CDV), a lymphotropic and neurotropic negative-stranded RNA virus of the Morbillivirus genus, causes a life-threatening disease in several carnivores, including domestic dogs. To identify the cellular receptor(s) involved in the uptake of CDV by susceptible cells, we isolated a monoclonal antibody (MAb K41) which binds to the cell surface and inhibits the CDV infection of several cell lines from various species. Pretreatment of cells with MAb K41 reduces the number of infectious centers and the size of the syncytia. Using affinity chromatography with MAb K41, we purified from HeLa and Vero cell extracts a 26-kDa protein which contained the amino acid sequence TKDEPQRETLK of human CD9, a member of the tetraspan transmembrane or transmembrane 4 superfamily of cell surface proteins. Transfection of NIH 3T3 or MDBK cells with a CD9 expression plasmid rendered these cells permissive for viral infection and raised virus production by a factor of 10 to 100. The mechanism involved is still unclear, since we were unable to detect direct binding of CDV to CD9 by using immunoprecipitation and a virus overlay protein binding assay. These findings indicate that human CD9 and its homologs in other species are necessary factors for the uptake of CDV by target cells, the formation of syncytia, and the production of progeny virus.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alexander K. A., Appel M. J. African wild dogs (Lycaon pictus) endangered by a canine distemper epizootic among domestic dogs near the Masai Mara National Reserve, Kenya. J Wildl Dis. 1994 Oct;30(4):481–485. doi: 10.7589/0090-3558-30.4.481. [DOI] [PubMed] [Google Scholar]
  2. Appel M. J. Pathogenesis of canine distemper. Am J Vet Res. 1969 Jul;30(7):1167–1182. [PubMed] [Google Scholar]
  3. Benoit P., Gross M. S., Frachet P., Frézal J., Uzan G., Boucheix C., Nguyen V. C. Assignment of the human CD9 gene to chromosome 12 (region P13) by use of human specific DNA probes. Hum Genet. 1991 Jan;86(3):268–272. doi: 10.1007/BF00202407. [DOI] [PubMed] [Google Scholar]
  4. Bolt G., Blixenkrone-Møller M. Nucleic acid hybridization analyses confirm the presence of a hitherto unknown morbillivirus in Mediterranean dolphins. Vet Microbiol. 1994 Aug 15;41(4):363–372. doi: 10.1016/0378-1135(94)90032-9. [DOI] [PubMed] [Google Scholar]
  5. Boucheix C., Benoit P., Frachet P., Billard M., Worthington R. E., Gagnon J., Uzan G. Molecular cloning of the CD9 antigen. A new family of cell surface proteins. J Biol Chem. 1991 Jan 5;266(1):117–122. [PubMed] [Google Scholar]
  6. Bradbury L. E., Kansas G. S., Levy S., Evans R. L., Tedder T. F. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol. 1992 Nov 1;149(9):2841–2850. [PubMed] [Google Scholar]
  7. Brown J. G., Almond B. D., Naglich J. G., Eidels L. Hypersensitivity to diphtheria toxin by mouse cells expressing both diphtheria toxin receptor and CD9 antigen. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8184–8188. doi: 10.1073/pnas.90.17.8184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brügger M., Jungi T. W., Zurbriggen A., Vandevelde M. Canine distemper virus increases procoagulant activity of macrophages. Virology. 1992 Oct;190(2):616–623. doi: 10.1016/0042-6822(92)90899-z. [DOI] [PubMed] [Google Scholar]
  9. Cerruti-Sola S., Kristensen F., Vandevelde M., Bichsel P., Kihm U. Lymphocyte responsiveness to lectin and myelin antigens in canine distemper infection in relation to the development of demyelinating lesions. J Neuroimmunol. 1983 Apr;4(2):77–90. doi: 10.1016/0165-5728(83)90013-9. [DOI] [PubMed] [Google Scholar]
  10. Distemper virus in Baikal seals. Nature. 1989 Mar 16;338(6212):209–210. doi: 10.1038/338209a0. [DOI] [PubMed] [Google Scholar]
  11. Dunster L. M., Schneider-Schaulies J., Löffler S., Lankes W., Schwartz-Albiez R., Lottspeich F., ter Meulen V. Moesin: a cell membrane protein linked with susceptibility to measles virus infection. Virology. 1994 Jan;198(1):265–274. doi: 10.1006/viro.1994.1029. [DOI] [PubMed] [Google Scholar]
  12. Dörig R. E., Marcil A., Chopra A., Richardson C. D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell. 1993 Oct 22;75(2):295–305. doi: 10.1016/0092-8674(93)80071-l. [DOI] [PubMed] [Google Scholar]
  13. Eckerskorn C., Mewes W., Goretzki H., Lottspeich F. A new siliconized-glass fiber as support for protein-chemical analysis of electroblotted proteins. Eur J Biochem. 1988 Oct 1;176(3):509–519. doi: 10.1111/j.1432-1033.1988.tb14308.x. [DOI] [PubMed] [Google Scholar]
  14. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  15. Haas L., Subbarao S. M., Harder T., Liess B., Barrett T. Detection of phocid distemper virus RNA in seal tissues using slot hybridization and the polymerase chain reaction amplification assay: genetic evidence that the virus is distinct from canine distemper virus. J Gen Virol. 1991 Apr;72(Pt 4):825–832. doi: 10.1099/0022-1317-72-4-825. [DOI] [PubMed] [Google Scholar]
  16. Harder T. C., Kenter M., Vos H., Siebelink K., Huisman W., van Amerongen G., Orvell C., Barrett T., Appel M. J., Osterhaus A. D. Canine distemper virus from diseased large felids: biological properties and phylogenetic relationships. J Gen Virol. 1996 Mar;77(Pt 3):397–405. doi: 10.1099/0022-1317-77-3-397. [DOI] [PubMed] [Google Scholar]
  17. Harrowe G., Sudduth-Klinger J., Payan D. G. Measles virus-substance P receptor interaction: Jurkat lymphocytes transfected with substance P receptor cDNA enhance measles virus fusion and replication. Cell Mol Neurobiol. 1992 Oct;12(5):397–409. doi: 10.1007/BF00711541. [DOI] [PubMed] [Google Scholar]
  18. Horejsí V., Vlcek C. Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63. FEBS Lett. 1991 Aug 19;288(1-2):1–4. doi: 10.1016/0014-5793(91)80988-f. [DOI] [PubMed] [Google Scholar]
  19. Imai T., Fukudome K., Takagi S., Nagira M., Furuse M., Fukuhara N., Nishimura M., Hinuma Y., Yoshie O. C33 antigen recognized by monoclonal antibodies inhibitory to human T cell leukemia virus type 1-induced syncytium formation is a member of a new family of transmembrane proteins including CD9, CD37, CD53, and CD63. J Immunol. 1992 Nov 1;149(9):2879–2886. [PubMed] [Google Scholar]
  20. Iwamoto R., Higashiyama S., Mitamura T., Taniguchi N., Klagsbrun M., Mekada E. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J. 1994 May 15;13(10):2322–2330. doi: 10.1002/j.1460-2075.1994.tb06516.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jennings L. K., Fox C. F., Kouns W. C., McKay C. P., Ballou L. R., Schultz H. E. The activation of human platelets mediated by anti-human platelet p24/CD9 monoclonal antibodies. J Biol Chem. 1990 Mar 5;265(7):3815–3822. [PubMed] [Google Scholar]
  22. Kersey J. H., LeBien T. W., Abramson C. S., Newman R., Sutherland R., Greaves M. P-24: a human leukemia-associated and lymphohemopoietic progenitor cell surface structure identified with monoclonal antibody. J Exp Med. 1981 Mar 1;153(3):726–731. doi: 10.1084/jem.153.3.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Krakowka S., Higgins R. J., Koestner A. Canine distemper virus: review of structural and functional modulations in lymphoid tissues. Am J Vet Res. 1980 Feb;41(2):284–292. [PubMed] [Google Scholar]
  24. Lanza F., Wolf D., Fox C. F., Kieffer N., Seyer J. M., Fried V. A., Coughlin S. R., Phillips D. R., Jennings L. K. cDNA cloning and expression of platelet p24/CD9. Evidence for a new family of multiple membrane-spanning proteins. J Biol Chem. 1991 Jun 5;266(16):10638–10645. [PubMed] [Google Scholar]
  25. Maisner A., Schneider-Schaulies J., Liszewski M. K., Atkinson J. P., Herrler G. Binding of measles virus to membrane cofactor protein (CD46): importance of disulfide bonds and N-glycans for the receptor function. J Virol. 1994 Oct;68(10):6299–6304. doi: 10.1128/jvi.68.10.6299-6304.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Manchester M., Liszewski M. K., Atkinson J. P., Oldstone M. B. Multiple isoforms of CD46 (membrane cofactor protein) serve as receptors for measles virus. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2161–2165. doi: 10.1073/pnas.91.6.2161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Manchester M., Valsamakis A., Kaufman R., Liszewski M. K., Alvarez J., Atkinson J. P., Lublin D. M., Oldstone M. B. Measles virus and C3 binding sites are distinct on membrane cofactor protein (CD46). Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2303–2307. doi: 10.1073/pnas.92.6.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Masellis-Smith A., Shaw A. R. CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin. J Immunol. 1994 Mar 15;152(6):2768–2777. [PubMed] [Google Scholar]
  29. Mitamura T., Iwamoto R., Umata T., Yomo T., Urabe I., Tsuneoka M., Mekada E. The 27-kD diphtheria toxin receptor-associated protein (DRAP27) from vero cells is the monkey homologue of human CD9 antigen: expression of DRAP27 elevates the number of diphtheria toxin receptors on toxin-sensitive cells. J Cell Biol. 1992 Sep;118(6):1389–1399. doi: 10.1083/jcb.118.6.1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Naniche D., Varior-Krishnan G., Cervoni F., Wild T. F., Rossi B., Rabourdin-Combe C., Gerlier D. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J Virol. 1993 Oct;67(10):6025–6032. doi: 10.1128/jvi.67.10.6025-6032.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Naniche D., Wild T. F., Rabourdin-Combe C., Gerlier D. Measles virus haemagglutinin induces down-regulation of gp57/67, a molecule involved in virus binding. J Gen Virol. 1993 Jun;74(Pt 6):1073–1079. doi: 10.1099/0022-1317-74-6-1073. [DOI] [PubMed] [Google Scholar]
  32. Orvell C., Sheshberadaran H., Norrby E. Preparation and characterization of monoclonal antibodies directed against four structural components of canine distemper virus. J Gen Virol. 1985 Mar;66(Pt 3):443–456. doi: 10.1099/0022-1317-66-3-443. [DOI] [PubMed] [Google Scholar]
  33. Osterhaus A. D., Groen J., De Vries P., UytdeHaag F. G., Klingeborn B., Zarnke R. Canine distemper virus in seals. Nature. 1988 Sep 29;335(6189):403–404. doi: 10.1038/335403a0. [DOI] [PubMed] [Google Scholar]
  34. Osterhaus A. D., de Swart R. L., Vos H. W., Ross P. S., Kenter M. J., Barrett T. Morbillivirus infections of aquatic mammals: newly identified members of the genus. Vet Microbiol. 1995 May;44(2-4):219–227. doi: 10.1016/0378-1135(95)00015-3. [DOI] [PubMed] [Google Scholar]
  35. Ozaki Y., Matsumoto Y., Yatomi Y., Higashihara M., Kume S. Two-step mobilization of arachidonic acid in platelet activation induced by low concentrations of TP 82, a monoclonal antibody against CD9 antigen. Eur J Biochem. 1991 Jul 15;199(2):347–354. doi: 10.1111/j.1432-1033.1991.tb16130.x. [DOI] [PubMed] [Google Scholar]
  36. Ozaki Y., Satoh K., Kuroda K., Qi R., Yatomi Y., Yanagi S., Sada K., Yamamura H., Yanabu M., Nomura S. Anti-CD9 monoclonal antibody activates p72syk in human platelets. J Biol Chem. 1995 Jun 23;270(25):15119–15124. doi: 10.1074/jbc.270.25.15119. [DOI] [PubMed] [Google Scholar]
  37. Rima B. K. The proteins of morbilliviruses. J Gen Virol. 1983 Jun;64(Pt 6):1205–1219. doi: 10.1099/0022-1317-64-6-1205. [DOI] [PubMed] [Google Scholar]
  38. Rima B. K., Wishaupt R. G., Welsh M. J., Earle J. A. The evolution of morbilliviruses: a comparison of nucleocapsid gene sequences including a porpoise morbillivirus. Vet Microbiol. 1995 May;44(2-4):127–134. doi: 10.1016/0378-1135(95)00005-u. [DOI] [PubMed] [Google Scholar]
  39. Roelke-Parker M. E., Munson L., Packer C., Kock R., Cleaveland S., Carpenter M., O'Brien S. J., Pospischil A., Hofmann-Lehmann R., Lutz H. A canine distemper virus epidemic in Serengeti lions (Panthera leo). Nature. 1996 Feb 1;379(6564):441–445. doi: 10.1038/379441a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rubinstein E., Le Naour F., Billard M., Prenant M., Boucheix C. CD9 antigen is an accessory subunit of the VLA integrin complexes. Eur J Immunol. 1994 Dec;24(12):3005–3013. doi: 10.1002/eji.1830241213. [DOI] [PubMed] [Google Scholar]
  41. Schneider-Schaulies J., Dunster L. M., Schwartz-Albiez R., Krohne G., ter Meulen V. Physical association of moesin and CD46 as a receptor complex for measles virus. J Virol. 1995 Apr;69(4):2248–2256. doi: 10.1128/jvi.69.4.2248-2256.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schneider-Schaulies J., Schnorr J. J., Brinckmann U., Dunster L. M., Baczko K., Liebert U. G., Schneider-Schaulies S., ter Meulen V. Receptor usage and differential downregulation of CD46 by measles virus wild-type and vaccine strains. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3943–3947. doi: 10.1073/pnas.92.9.3943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schroeder C. Substance P, a neuropeptide, inhibits measles virus replication in cell culture. Acta Virol. 1986 Sep;30(5):432–435. [PubMed] [Google Scholar]
  44. Seehafer J. G., Shaw A. R. Evidence that the signal-initiating membrane protein CD9 is associated with small GTP-binding proteins. Biochem Biophys Res Commun. 1991 Aug 30;179(1):401–406. doi: 10.1016/0006-291x(91)91384-o. [DOI] [PubMed] [Google Scholar]
  45. Slupsky J. R., Seehafer J. G., Tang S. C., Masellis-Smith A., Shaw A. R. Evidence that monoclonal antibodies against CD9 antigen induce specific association between CD9 and the platelet glycoprotein IIb-IIIa complex. J Biol Chem. 1989 Jul 25;264(21):12289–12293. [PubMed] [Google Scholar]
  46. Stern L. B., Greenberg M., Gershoni J. M., Rozenblatt S. The hemagglutinin envelope protein of canine distemper virus (CDV) confers cell tropism as illustrated by CDV and measles virus complementation analysis. J Virol. 1995 Mar;69(3):1661–1668. doi: 10.1128/jvi.69.3.1661-1668.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Summers B. A., Appel M. J. Aspects of canine distemper virus and measles virus encephalomyelitis. Neuropathol Appl Neurobiol. 1994 Dec;20(6):525–534. doi: 10.1111/j.1365-2990.1994.tb01006.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vandevelde M., Zurbriggen A. The neurobiology of canine distemper virus infection. Vet Microbiol. 1995 May;44(2-4):271–280. doi: 10.1016/0378-1135(95)00021-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Willett B. J., Hosie M. J., Jarrett O., Neil J. C. Identification of a putative cellular receptor for feline immunodeficiency virus as the feline homologue of CD9. Immunology. 1994 Feb;81(2):228–233. [PMC free article] [PubMed] [Google Scholar]
  50. Wiśniewski H., Raine C. S., Kay W. J. Observations on viral demyelinating encephalomyelitis. Canine distemper. Lab Invest. 1972 May;26(5):589–599. [PubMed] [Google Scholar]
  51. Yatomi Y., Higashihara M., Ozaki Y., Kume S., Kurokawa K. Intracellular ionized calcium mobilization of CD 9 monoclonal antibody-activated human platelets. Biochem Biophys Res Commun. 1990 Aug 31;171(1):109–115. doi: 10.1016/0006-291x(90)91363-w. [DOI] [PubMed] [Google Scholar]
  52. Yatomi Y., Ozaki Y., Satoh K., Kume S. Anti-CD9 monoclonal antibody elicits staurosporine inhibitable phosphatidylinositol 4,5-bisphosphate hydrolysis, phosphatidylinositol 3,4-bisphosphate synthesis, and protein-tyrosine phosphorylation in human platelets. FEBS Lett. 1993 May 17;322(3):285–290. doi: 10.1016/0014-5793(93)81587-p. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES